Combination therapy using azabicyclo compound for cancer

ABSTRACT

Provided is a novel method for treating cancer using an HSP90 inhibitor which exhibits a markedly superior antitumor effect and has a reduced side effect.An antitumor agent is characterized in that an azabicyclo compound of the following Formula (1) or a salt thereof is administered in combination with other antitumor agent(s).

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No. 15/493,479, filed Apr. 21, 2017, which is a continuation of U.S. patent application Ser. No. 15/025,797, filed Mar. 29, 2016, which is the National Stage of the International Patent Application No. PCT/JP2014/075846, filed Sep. 29, 2014, and claims priority to Japanese Application No. 2013-205500, filed Sep. 30, 2013, the disclosures of all of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to an antitumor agent containing a combination of an azabicyclo compound or a salt thereof and other antitumor agent(s), and an antitumor effect potentiator for other antitumor agent(s).

BACKGROUND ART

A group of proteins called molecular chaperons is a multifunctional protein, which promotes the formation of the functional structures of other proteins or maintains these structures, promotes correct association, inhibits unnecessary aggregation, protects other proteins from degradation, and promotes secretion (Non Patent Literature 1). HSP90 is a molecular chaperon as abundant as approximately 1 to 2% of all intracellular soluble proteins and is however unnecessary for the biosynthesis of the majority of polypeptides, unlike other chaperon proteins (Non Patent Literature 1). Signaling-related factors (for example, ERBB1/EGFR, ERBB2/HER2, MET, IGF1R, KDR/VEGFR, FLT3, ZAP70, KIT, CHUK/IKK, BRAF, RAF1, SRC, and AKT), cell cycle regulators (for example, CDK4, CDK6, Cyclin D, PLK1, and BIRC5), and transcriptional regulators (for example, HIF-1α, p53, androgen receptor, estrogen receptor, and progesterone receptor) are known as the main client proteins whose structure formation or stability is regulated by HSP90 through the interaction therebetween (Non Patent Literatures 2 and 3). HSP90 is deeply involved in cell proliferation or survival by maintaining the normal functions of these proteins. Furthermore, HSP90 is required for the normal functions of mutated or chimeric factors (for example, BCR-ABL and NPM-ALK) which cause carcinogenesis or exacerbation of cancer. This indicates the importance of HSP90 particularly for processes such as carcinogenesis, cancer survival, growth, exacerbation, and metastasis (Non Patent Literature 2).

The inhibition of the chaperon functions of HSP90 by specific inhibitors such as geldanamycin causes the inactivation, destabilization, and degradation of the client proteins, resulting in induction of a halt in cell proliferation or apoptosis (Non Patent Literature 4). In terms of the physiological functions of HSP90, HSP90 inhibitors are characterized in that they can simultaneously inhibit multiple signaling pathways involved in cancer survival and growth. Thus, the HSP90 inhibitors can serve as pharmaceuticals having extensive and effective anticancer activity. Moreover, from the findings that cancer cell-derived HSP90 has higher activity and higher affinity for ATP or inhibitors than those of normal cell-derived HSP90, it has been expected that the HSP90 inhibitors would serve as pharmaceuticals having high cancer selectivity (Non Patent Literature 5). Currently, the clinical development of multiple HSP90 inhibitors as anticancer agents is ongoing. The most advancing Ganetespib is under development as single agents as well as under test on the combined use with other antitumor agents such as docetaxel (Non Patent Literature 6).

Further, a new type of HSP90 inhibitor has been reported (Patent Literature 1), and HSP90 inhibitors with higher antitumor effects and reduced side effects have been desired.

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2011/004610 A

Non Patent Literatures

-   Non Patent Literature 1: Nature Reviews Cancer 5, 761-772(2005) -   Non Patent Literature 2: TRENDS in Molecular Medicine 10(6), 283-290     (2004) -   Non Patent Literature 3: Clin Can Res 15, 9-14(2009) -   Non Patent Literature 4: Current Opinion in Pharmacology 8,     370-374(2008) -   Non Patent Literature 5: Drug Resistance Updates 12, 17-27(2009) -   Non Patent Literature 6: Invest New Drugs. 30(6):2201-9(2012)

SUMMARY OF INVENTION Technical Problem

An object of the invention is to provide a method of using HSP90 inhibitors with high antitumor effects and reduced side effects.

Solution to Problem

The present inventors examined combined use of various HSP90 inhibitors and other antitumor agent(s) under the circumstances. As a result, they found that an azabicyclo compound having an HSP90 inhibitory agent remarkably potentiates the antitumor effect of extremely various ranges of antitumor agents having different action mechanisms.

That is, the invention provides the following [1] to [36].

[1] An antitumor agent, where an azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ represents CH or N;

any one of X², X³, and X⁴ is N, and the others represent CH;

any one or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are the same or different and represent CH or N;

R¹ represents an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O;

R² represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, or an optionally substituted alkenyl group having 2 to 6 of carbon atom;

R³ represents a cyano group or —CO—R⁵;

R⁴(s) are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 of carbon atom, an alkenyl group having 2 to 6 of carbon atom, an alkoxy group having 1 to 6 of carbon atom, an aromatic hydrocarbon group, —N(R⁶)(R⁷), —S—R⁸, or —CO—R⁹;

R⁵ represents an amino group optionally having a hydroxyl group or an optionally substituted mono- or di-alkylamino group;

R⁶ and R⁷ are the same or different and represent a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, a halogenoalkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted saturated heterocyclic group, or an optionally substituted unsaturated heterocyclic group, or R⁶ and R⁷ optionally form a saturated heterocyclic group together with a nitrogen atom to which they are bonded;

R⁸ represents an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group; and

R⁹ represents a hydrogen atom, a hydroxyl group, an amino group optionally having a hydroxyl group, or an optionally substituted mono- or di-alkylamino group, is administered in combination with other antitumor agent(s).

[2] The antitumor agent according to [1], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other is CH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, an optionally substituted pyrazol-4-yl group, an optionally substituted thiophen-3-yl group, an optionally substituted furan-2-yl group, an optionally substituted pyridin-3-yl group, an optionally substituted pyridin-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, an optionally substituted benzofuran-2-yl group, an optionally substituted quinolin-3-yl group, and an optionally substituted 5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having a halogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atom optionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group together with a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- or di-(C1-C6 alkyl)amino group.

[3] The antitumor agent according to [1] or [2], where the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[4] The antitumor agent according to any one of [1] to [3], where the other antitumor agent is one or more of kind(s) selected from the group consisting of an antitumor antibiotic substance, a platinum-based agent, a pyrimidine-based antimetabolite agent, a purine-based antimetabolite agent, a folic acid antimetabolite agent, a plant alkaloid-based antitumor agent, an immunomodulating drug, and a low molecular weight molecular targeted drug.

[5] The antitumor agent according to any one of [1] to [4], where the other antitumor agent is one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.

[6] The antitumor agent according to any one of [1] to [5], where the azabicyclo compound or a salt thereof and the other antitumor agent are administered to a cancer patient simultaneously or separately at an interval.

[7] An antitumor effect potentiator for other antitumor agent(s), containing an azabicyclo compound or a salt thereof, in which

the azabicyclo compound is a compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, and R¹ to R³ are as defined above.

[8] An antitumor agent containing an azabicyclo compound or a salt thereof, which is used for treating a cancer patient who has been administered other antitumor agent (s), in which

the azabicyclo compound is an azabicyclo compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[9] An antitumor agent containing a combination of an azabicyclo compound or a salt thereof and other antitumor agent(s), in which

the azabicyclo compound is an azabicyclo compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[10] An azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for treating a tumor by administration in combination with other antitumor agent(s).

[11] The compound according to [10] or a salt thereof, where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other is CH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, an optionally substituted pyrazol-4-yl group, an optionally substituted thiophen-3-yl group, an optionally substituted furan-2-yl group, an optionally substituted pyridin-3-yl group, an optionally substituted pyridin-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, an optionally substituted benzofuran-2-yl group, an optionally substituted quinolin-3-yl group, and an optionally substituted 5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having a halogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atom optionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group together with a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- or di-(C1-C6 alkyl)amino group.

[12] The compound according to [10] or [11] or a salt thereof, where the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[13] The compound according to any one of [10] to [12] or a salt thereof, where the other antitumor agent is one or more of kind(s) selected from the group consisting of an antitumor antibiotic substance, a platinum-based agent, a pyrimidine-based antimetabolite agent, a purine-based antimetabolite agent, a folic acid antimetabolite agent, a plant alkaloid-based antitumor agent, an immunomodulating drug, and a low molecular weight molecular targeted drug.

[14] The compound according to any one of [10] to [13] or a salt thereof, where the other antitumor agent is one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.

[15] The compound according to any one of [10] to [14] or a salt thereof, where the azabicyclo compound or a salt thereof and the other antitumor agent are administered to a cancer patient simultaneously or separately at an interval.

[16] A compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for potentiating the antitumor effect of other antitumor agent(s).

An azabicyclo compound of the following Formula (I) or a salt thereof, which is used for treating a cancer patient who has been administered other antitumor agent(s):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[18] An azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for treating a tumor in combination with other antitumor agent(s).

[19] Use of an azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor agent to be administered in combination with other antitumor agent(s).

[20] The use according to [19], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other is CH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, an optionally substituted pyrazol-4-yl group, an optionally substituted thiophen-3-yl group, an optionally substituted furan-2-yl group, an optionally substituted pyridin-3-yl group, an optionally substituted pyridin-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, an optionally substituted benzofuran-2-yl group, an optionally substituted quinolin-3-yl group, and an optionally substituted 5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having a halogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atom optionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group together with a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- or di-(C1-C6 alkyl)amino group.

[21] The use according to [19] or [20], where the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[22] The use according to any one of [19] to [21], where the other antitumor agent is one or more of kind(s) selected from the group consisting of an antitumor antibiotic substance, a platinum-based agent, a pyrimidine-based antimetabolite agent, a purine-based antimetabolite agent, a folic acid antimetabolite agent, a plant alkaloid-based antitumor agent, an immunomodulating drug, and a low molecular weight molecular targeted drug.

[23] The use according to any one of [19] to [22], where the other antitumor agent is one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.

[24] The use according to any one of [19] to [23], where the azabicyclo compound or a salt thereof and the other antitumor agent are administered to a cancer patient simultaneously or separately at an interval.

[25] Use of a compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor effect potentiator f or other antitumor agent(s).

[26] Use of an azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor agent for treating a cancer patient who has been administered other antitumor agent (s).

[27] Use of an azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above,

which is used for producing an antitumor agent by combining other antitumor agent(s).

[28] A method for treating a tumor, including administrating an azabicyclo compound of the following Formula (I) or a salt thereof:

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above, and other antitumor agent(s), in combination.

[29] The treating method according to [28], where

the azabicyclo compound is a compound of Formula (I),

in the formula, X¹ is CH or N;

X² is N and X³ and X⁴ are CH;

Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other is CH;

R¹ is any of an optionally substituted 1H-imidazol-1-yl group, an optionally substituted pyrazol-4-yl group, an optionally substituted thiophen-3-yl group, an optionally substituted furan-2-yl group, an optionally substituted pyridin-3-yl group, an optionally substituted pyridin-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, an optionally substituted benzofuran-2-yl group, an optionally substituted quinolin-3-yl group, and an optionally substituted 5,6,7,8-tetrahydroquinolin-3-yl group;

R² is an alkyl group having 1 to 6 of carbon atom optionally having a halogen atom or an alkenyl group having 2 to 6 of carbon atom;

R³ is —CO—R⁵;

R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atom optionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹;

R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group;

R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom;

R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group together with a nitrogen atom to which they are bonded;

R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom; and

R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- or di-(C1-C6 alkyl)amino group.

[30] The treating method according to [28], where the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide.

[31] The treating method according to [28], where the other antitumor agent is one or more of kind(s) selected from the group consisting of an antitumor antibiotic substance, a platinum-based agent, a pyrimidine-based antimetabolite agent, a purine-based antimetabolite agent, a folic acid antimetabolite agent, a plant alkaloid-based antitumor agent, an immunomodulating drug, and a low molecular weight molecular targeted drug.

[32] The treating method according to [28], where the other antitumor agent is one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.

[33] The treating method according to any one of [28] to [32], where the azabicyclo compound or a salt thereof and the other antitumor agent are administered to a cancer patient simultaneously or separately at an interval.

[34] A method for potentiating the antitumor effect of other antitumor agent(s), including administering an azabicyclo compound or a salt thereof, in which the azabicyclo compound is a compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[35] A method for treating a tumor, including administering an azabicyclo compound or a salt thereof to a cancer patient who has been administered other antitumor agent(s), in which

the azabicyclo compound is an azabicyclo compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

[36] A method for treating a tumor, including administering an azabicyclo compound or a salt thereof and other antitumor agent(s), in combination, in which

the azabicyclo compound is an azabicyclo compound of the following Formula (I):

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

Advantageous Effects of Invention

The antitumor agent of the invention serves to perform cancer therapy exhibiting high antitumor effect while suppressing side effects, and, thus, the survival of a cancer patient can be prolonged.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an effect of the combination of Compound 1 and docetaxel with respect to the rate of tumor growth of a human non-small cell lung cancer line NCI-H2170.

FIG. 2 shows an effect of the combination of Compound 1 and paclitaxel with respect to the rate of tumor growth of a human non-small cell lung cancer line NCI-H441.

FIG. 3 shows an effect of the combination of Compound 1 and cisplatin with respect to the rate of tumor growth of a human stomach cancer line NCI-N87.

FIG. 4 shows an effect of the combination of Compound 1 and amrubicin with respect to the rate of tumor growth of a human small cell lung cancer cell line SBC-1.

DESCRIPTION OF EMBODIMENTS

The HSP90 inhibitor in the invention, which provides an excellent synergic effect with other antitumor agent(s), is an azabicyclo compound of the following Formula (I) and a salt thereof.

in the formula, X¹ to X⁴, Y¹ to Y⁴, R¹ to R³ are as defined above.

In the present specification, examples of “substituents” include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a halogenoalkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenoalkoxy group, an alkoxy-alkyl group, a cycloalkoxy group, a cycloalkyl-alkoxy group, an aralkyloxy group, an aralkyloxy-alkyl group, an alkylthio group, a cycloalkyl-alkylthio group, an amino group, a mono- or dialkylamino group, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group, an oxo group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a saturated or unsaturated heterocyclic group, an aromatic hydrocarbon group, and a saturated heterocyclic oxy group. When the above substituent is present, the number of the substituents is typically 1 to 3.

Examples of the halogen atom included in the substituents include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.

The alkyl group or the halogenoalkyl group included in the substituents preferably refers to a linear or branched alkyl group having 1 to 6 of carbon atom or a group in which one or all hydrogen atom(s) in such an alkyl group are substituted by the halogen atom described above. Examples thereof include alkyl groups such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group and halogenoalkyl groups such as a trifluoromethyl group.

The cycloalkyl group included in the substituents is preferably a cycloalkyl group having 3 to 7 of carbon atom, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

The cycloalkyl-alkyl group included in the substituents is preferably an alkyl group having 1 to 6 of carbon atom which is substituted by cycloalkyl having 3 to 7 of carbon atom, and examples thereof include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.

The aralkyl group included in the substituents preferably refers to a linear or branched alkyl group having 1 to 6 of carbon atom which is substituted by an aromatic hydrocarbon group having 6 to 14 of carbon atom, and examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, and a naphthylethyl group.

The hydroxyalkyl group included in the substituents preferably refers to the linear or branched alkyl group having 1 to 6 of carbon atom described which has a hydroxy group, and examples thereof include a hydroxymethyl group and a hydroxyethyl group.

The alkenyl group included in the substituents preferably refers to an alkenyl group having 2 to 6 of carbon atom which contains a carbon-carbon double bond, and examples thereof include a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.

The alkynyl group included in the substituents preferably refers to an alkynyl group having 2 to 6 of carbon atom which contains a carbon-carbon triple bond, and examples thereof include an ethynyl group and a propargyl group.

The alkoxy group or the halogenoalkoxy group included in the substituents preferably refers to a linear or branched alkoxy group having 1 to 6 of carbon atom, or a group in which such an alkoxy group is substituted by the halogen atom described above, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a 1-methylpropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a 2-methyl-butoxy group, a neopentyloxy group, a pentan-2-yloxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1,1-difluoroethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a perfluoroethoxy group, a 3-fluoro-2-(fluoromethyl)-propoxy group, a 1,3-difluoropropan-2-yloxy group, and a 2,2,3,3,3-pentafluoro-1-propoxy group.

The cycloalkoxy group included in the substituents is preferably a cycloalkoxy group having 3 to 7 of carbon atom, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group.

The alkoxy-alkyl group included in the substituents preferably refers to the alkyl group having 1 to 6 of carbon atom described above which is substituted by the linear or branched alkoxy group having 1 to 6 of carbon atom described above, and examples thereof include a methoxymethyl group and an ethoxymethyl group.

The cycloalkyl-alkoxy group included in the substituents is preferably an alkoxy group having 1 to 6 of carbon atom which is substituted by cycloalkyl having 3 to 7 of carbon atom, and examples thereof include a cyclopropylmethoxy group, a cyclopropylethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, and a cyclohexylmethoxy group.

The aralkyloxy group included in the substituents preferably refers to an oxy group which has the aralkyl group described above, and examples thereof include a benzyloxy group, a phenethyloxy group, a phenylpropyloxy group, a naphthylmethyloxy group, and a naphthylethyloxy group.

The aralkyloxy-alkyl group included in the substituents preferably refers to the linear or branched alkyl group having 1 to 6 of carbon atom described above which has the aralkyloxy group described above, and examples thereof include a benzyloxymethyl group and a benzyloxyethyl group.

The alkylthio group included in the substituents is preferably a (C1-C6) alkylthio group which refers to a linear or branched alkylthio group having 1 to 6 of carbon atom, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, a pentylthio group, and a hexylthio group.

The cycloalkyl-alkylthio group included in the substituents is preferably an alkylthio group having 1 to 6 of carbon atom which is substituted by cycloalkyl having 3 to 7 of carbon atom, and examples thereof include a cyclopropylmethylthio group, a cyclopropylethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, and a cyclohexylmethylthio group.

The mono- or dialkylamino group included in the substituents is a mono- or di-(C1-C6 alkyl)amino group which refers to an amino group which is monosubstituted or disubstituted by the linear or branched alkyl group having 1 to 6 of carbon atom described above, and examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, and a methylethylamino group.

The cycloalkyl-alkylamino group included in the substituents refers to an alkylamino group which is substituted by the cycloalkyl group described above, and examples thereof include a cyclopropylmethylamino group, a cyclobutylmethylamino group, and a cyclopentylmethylamino group.

Examples of the acyl group included in the substituents include: linear or branched acyl groups having 1 to 6 of carbon atom such as a formyl group, an acetyl group, a propionyl group, an n-butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group; and a benzoyl group.

Examples of the acyloxy group included in the substituents include: linear or branched acyloxy groups having 1 to 6 of carbon atom such as a formyloxy group, an acetoxy group, a propionyloxy group, an n-butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovaleryloxy group, and a pivaloyloxy group; a benzoyloxy group; and amino acid-derived acyloxy groups such as a glycyloxy group, an alanyloxy group, and a leucyloxy group.

The alkoxycarbonyl group included in the substituents refers to a carbonyl group which is substituted by the alkoxy group described above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, a 1-methylpropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a 2-methyl-butoxycarbonyl group, a neopentyloxycarbonyl group, and a pentan-2-yloxycarbonyl group.

The aralkyloxycarbonyl group included in the substituents preferably refers to a carbonyl group which is substituted by the aralkyloxy group described above, and examples thereof include a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a phenylpropyloxycarbonyl group, a naphthylmethyloxycarbonyl group, and a naphthylethyloxycarbonyl group.

Examples of the carbamoyl group in the substituents include a —CONH₂ group, a (mono- or dialkyl)carbamoyl group, a (mono- or diaryl)carbamoyl group, an (N-alkyl-N-aryl)carbamoyl group, a pyrrolidinocarbamoyl group, a piperidinocarbamoyl group, a piperazinocarbamoyl group, and a morpholinocarbamoyl group.

The saturated or unsaturated heterocyclic group included in the substituents refers to a mono- or bi-cyclic saturated or 5- to 10-membered unsaturated heterocyclic group preferably having 1 to 4 of any heteroatom of N, S and O, and examples thereof include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperazinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an imidazolyl group, a thienyl group, a furyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrazyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a benzofuranyl group, a dihydrobenzofuranyl group, a benzoimidazolyl group, a benzooxazolyl group, a benzothiazolyl group, a purinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, and a quinoxalyl group.

The aromatic hydrocarbon group included in the substituents preferably refers to an aromatic hydrocarbon group having 6 to 14 of carbon atom, and examples thereof include a phenyl group and a naphthyl group.

The saturated heterocyclic oxy group included in the substituents refers to a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S and O, for example, an oxy group which has a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, or a homopiperazinyl group. Examples thereof include a tetrahydrofuranyloxy group and a tetrahydropyranyloxy group.

In Formula (I), X¹ represents CH or N. Moreover, in Formula (I), any one of X², X³, and X represents N, and the others represent CH. Based on these definitions of X¹ to X⁴, examples of the azabicyclo skeleton in Formula (I) include the following structures:

in the formula, R¹ and R² are as defined above.

Among these skeletons, (A-3) and (A-6) are particularly preferable.

In Formula (I), the “mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O” in the “optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O” represented by R¹ is preferably a mono- or bi-cyclic 5- to 10-membered unsaturated heterocyclic group having 1 to 3 of heteroatom selected from the group consisting of N, S, and O, more preferably a monocyclic 5- to 6-membered unsaturated heterocyclic group having 1 to 3 of heteroatom selected from the group consisting of N, S, and O, or a bicyclic 9- to 10-membered unsaturated heterocyclic group having 1 to 3 of heteroatom selected from the group consisting of N, S, and O. The heterocyclic group is preferably a group having imidazole, pyrazole, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, pyrrolopyridine, indazole, methylenedioxyphenyl, ethylenedioxyphenyl, benzofuran, dihydrobenzofuran, benzimidazol, benzoxazol, benzothiazole, purine, quinoline, tetrahydroquinoline, isoquinoline, quinazoline, or quinoxaline, more preferably a group having imidazol, pyrazol, thiophene, furan, pyridine, indole, pyrrolopyridine, benzofuran, quinoline, or tetrahydroquinoline, and particularly preferably a group having imidazol, pyridine, or quinoline.

Specific examples thereof include a 1H-imidazol-1-yl group, a 1H-imidazol-2-yl group, a 1H-imidazol-4-yl group, a 1H-pyrazol-1-yl group, a 1H-pyrazol-3-yl group, a 1H-pyrazol-4-yl group, a thiophen-2-yl group, a thiophen-3-yl group, a furan-2-yl group, a furan-3-yl group, a pyrrol-1-yl group, a pyrrol-2-yl group, a pyrrol-3-yl group, an oxazol-2-yl group, an oxazol-4-yl group, an oxazol-5-yl group, an isoxazol-3-yl group, an isoxazol-4-yl group, an isoxazol-5-yl group, a thiazol-2-yl group, a thiazol-3-yl group, a thiazol-4-yl group, a thiazol-5-yl group, an isothiazol-2-yl group, an isothiazol-4-yl group, an isothiazol-5-yl group, a pyrazol-1-yl group, a pyrazol-3-yl group, a pyrazol-4-yl group, a 1,2,3-triazol-1-yl group, a 1,2,3-triazol-4-yl group, a 1,2,4-triazol-1-yl group, a 1,2,4-triazol-3-yl group, a 1,2,4-triazol-4-yl group, a tetrazol-1-yl group, a tetrazol-5-yl group, a pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a pyrazin-2-yl group, a pyrazin-3-yl group, a pyrimidin-2-yl group, a pyrimidin-4-yl group, a pyrimidin-5-yl group, a pyrimidin-6-yl group, a pyridazin-3-yl group, a pyridazin-4-yl group, an indol-1-yl group, an indol-2-yl group, an indol-3-yl group, an indol-4-yl group, an indol-5-yl group, an indol-6-yl group, an indol-7-yl group, an isoindol-1-yl group, an isoindol-2-yl group, an isoindol-4-yl group, an isoindol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-1-yl group, a 1H-pyrrolo[2,3-b]pyridin-2-yl group, a 1H-pyrrolo[2,3-b]pyridin-3-yl group, a 1H-pyrrolo[2,3-b]pyridin-4-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-6-yl group, a 1H-indazol-1-yl group, a 1H-indazol-3-yl group, a 1H-indazol-4-yl group, a 1H-indazol-5-yl group, a 1H-indazol-6-yl group, a 1H-indazol-7-yl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a benzofuran-2-yl group, a benzofuran-3-yl group, a benzofuran-4-yl group, a benzofuran-5-yl group, a benzofuran-6-yl group, a benzofuran-7-yl group, a 2,3-dihydrobenzofuran-2-yl group, a 2,3-dihydrobenzofuran-3-yl group, a benzimidazol-1-yl group, a benzimidazol-2-yl group, a benzimidazol-4-yl group, a benzimidazol-5-yl group, a benzoxazol-2-yl group, a benzoxazol-4-yl group, a benzoxazol-5-yl group, a benzothiazol-2-yl group, a benzothiazol-4-yl group, a benzothiazol-5-yl group, a purin-2-yl group, a purin-6-yl group, a purin-7-yl group, a purin-8-yl group, a quinolin-2-yl group, quinolin-3-yl group, a quinolin-4-yl group, quinolin-5-yl group, a quinolin-6-yl group, a quinolin-7-yl group, a quinolin-8-yl group, a 5,6,7,8-tetrahydroquinolin-2-yl group, a 5,6,7,8-tetrahydroquinolin-3-yl group, a 5,6,7,8-tetrahydroquinolin-4-yl group, an isoquinolin-1-yl group, an isoquinolin-3-yl group, an isoquinolin-4-yl group, an isoquinolin-5-yl group, an isoquinolin-6-yl group, an isoquinolin-7-yl group, an isoquinolin-8-yl group, a quinazolin-4-yl group, a quinoxalin-2-yl group, a quinoxalin-5-yl group, and a quinoxalin-6-yl group. A 1H-imidazol-1-yl group, a pyrazol-4-yl group, a thiophen-3-yl group, a furan-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, an indol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a benzofuran-2-yl group, a quinolin-3-yl group, and 5,6,7,8-tetrahydroquinolin-3-yl group are preferable, a 1H-imidazol-1-yl group, a pyridin-3-yl group, a pyridin-4-yl group, an indol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a benzofuran-2-yl group, a quinolin-3-yl group, and a 5,6,7,8-tetrahydroquinolin-3-yl group are more preferable, and a 1H-imidazol-1-yl group, a pyridin-3-yl group, and a quinolin-3-yl group are particularly preferable.

In Formula (I), examples of the “substituent(s)” in the unsaturated heterocyclic group represented by R¹ include the substituents described above. The substituent(s) are preferably 1 to 3 of substituent selected from the group consisting of an alkyl group, an alkoxy group, an alkoxy-alkyl group, an aralkyl group, an aralkyloxy-alkyl group, a halogen atom, a halogenoalkyl group, an acyl group, an optionally substituted saturated or unsaturated heterocyclic group, and an optionally substituted aromatic hydrocarbon group, and more preferably 1 to 3 of substituent selected from the group consisting of an alkyl group; an alkoxy group; an unsaturated heterocyclic group optionally having an alkyl group, a halogenoalkyl group, an aralkyl group, or a hydroxyalkyl group; and an aromatic hydrocarbon group optionally having an alkyl group, an alkoxy group, or a carbamoyl group. Herein, examples of the unsaturated heterocyclic group which may be substituted on the unsaturated heterocyclic ring represented by R¹ include pyrazol, imidazol, pyridine, pyrimidine, furan, and thiophene. In addition, examples of the aromatic hydrocarbon group include phenyl and naphthyl.

Specific examples of the “substituent(s)” in the unsaturated heterocyclic group represented by R¹ can include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a 1-methylpropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a 1H-pyrazol-4-yl group, a 1-methyl-1H-pyrazol-4-yl group, a 1-ethyl-1H-pyrazol-4-yl group, a 1-isopropyl-1H-pyrazol-4-yl group, a 1-benzyl-1H-pyrazol-4-yl group, a 1-(difluoromethyl)-1H-pyrazol-4-yl group, a 1-(hydroxyethyl)-1H-pyrazol-4-yl group, a 1H-imidazol-1-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a pyrimidin-5-yl group, a furan-2-yl group, a furan-3-yl group, a thiophen-3-yl group, a phenyl group, a 4-methoxyphenyl group, a 4-carbamoylphenyl group, a 4-isopropylcarbamoylphenyl group, and a 4-dimethylcarbamoylphenyl group.

Specific examples of preferable R¹ include a 1H-imidazol-1-yl group, a 4-phenyl-1H-imidazol-1-yl group, a 4-(4-carbamoylphenyl)-1H-imidazol-1-yl group, a 4-(4-methoxyphenyl)-1H-imidazol-1-yl group, a 4-(thiophene-3-yl)-1H-imidazol-1-yl group, a 4-(pyridin-3-yl)-1H-imidazol-1-yl group, a 4-(pyridin-4-yl)-1H-imidazol-1-yl group, a 5-methyl-4-(pyridin-3-yl)-1H-imidazol-1-yl group, a 4-(pyrimidin-5-yl)-1H-imidazol-1-yl group, a 4-(furan-2-yl)-1H-imidazol-1-yl group, a 4-(furan-3-yl)-1H-imidazol-1-yl group, a 4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(l-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-ethyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-isopropyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-hydroxymethyl)-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-(hydroxyethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-(hydroxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-benzyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-(benzyloxyethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 1′H-1,4′-biimidazol-1′-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a 5-methoxypyridin-3-yl group, a 6-methoxypyridin-3-yl group, a 1-benzyl-1H-pyrazol-4-yl group, a 1-methyl-1H-indol-5-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, a 1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, a 5,6,7,8-tetrahydroquinolin-3-yl group, a quinolin-3-yl group, a thiophen-3-yl group, a furan-2-yl group, and a benzofuran-2-yl group. R¹ is more preferably a 1H-imidazol-1-yl group, a 4-(pyridin-3-yl)-1H-imidazol-1-yl group, a 4-(pyridin-4-yl)-1H-imidazol-1-yl group, a 4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-ethyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-isopropyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(1-benzyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a quinolin-3-yl group, and a 4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl group, and particularly preferably a 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl group, a 4-(pyridin-3-yl)-1H-imidazol-1-yl group, and a quinolin-3-yl group.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R² refers to a linear or branched alkyl group having 1 to 6 of carbon atom, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, or a hexyl group, and is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

Examples of the “substituent(s)” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R² include the substituents described above. Among these, the substituent(s) are preferably a halogen atom.

The halogen atom-substituted alkyl group is preferably a halogenoalkyl group having 1 to 6 of carbon atom, and more preferably a trifluoromethyl group.

The “alkenyl group having 2 to 6 of carbon atom” represented by R² refers to the alkenyl group having 2 to 6 of carbon atom described above, and is preferably a vinyl group. Examples of the substituent(s) in the alkenyl group include the substituents described above.

R² is more preferably an optionally substituted alkyl group having 1 to 6 of carbon atom or an optionally substituted alkenyl group having 2 to 6 of carbon atom, even more preferably an alkyl group having 1 to 6 of carbon atom which optionally has a halogen atom, or an alkenyl group having 2 to 6 of carbon atom, and particularly preferably an alkyl group having 1 to 4 of carbon atom which optionally has a halogen atom.

Any one or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are the same or different and represent CH or N. Among these, preferably, any one or two of Y¹, Y², Y³, and Y⁴ are C—R⁴, and the others are CH. More preferably, Y¹ and Y³ are CH, any one or two of Y^(a) and Y⁴ are C—R⁴, and the others are CH. These preferable aspects are represented by the following formulae:

in the formula, R³ and R⁴ are as defined above.

Among these, (b1) and (b2) are particularly preferable.

In Formula (I), R³ represents a cyano group or —CO—R⁵. Among these, —CO—R⁵ is particularly preferable

In Formula (I), R⁴(s) are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 of carbon atom, a cycloalkyl group having 3 to 7 of carbon atom, an alkenyl group having 2 to 6 of carbon atom, an alkoxy group having 1 to 6 of carbon atom, an aromatic hydrocarbon group, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹. Among these, R⁴ is preferably a halogen atom, an alkyl group having 1 to 6 of carbon atom which optionally has a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹, and more preferably a halogen atom, an alkyl group having 1 to 6 of carbon atom, or —N(R⁶) (R⁷).

In Formula (I), the “halogen atom” represented by R⁴ refers to the halogen atom described above and is preferably a chlorine atom.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R⁴ refers to the alkyl group having 1 to 6 of carbon atom described above and is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. Examples of the “substituent(s)” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R⁴ include the substituents described above. The “substituent(s)” are preferably mono- or di-(C1-C6 alkyl)amino groups such as an ethylamino group and a dimethylamino group or monocyclic 5- to 7-membered saturated heterocyclic groups having one or two of any heteroatom of N, S, and O such as a pyrrolidyl group and morpholino group.

In Formula (I), the “cycloalkyl group having 3 to 7 of carbon atom” represented by R⁴ refers to the cycloalkyl group having 3 to 7 of carbon atom described above and is preferably a cyclopropyl group.

In Formula (I), the “alkenyl group having 2 to 6 of carbon atom” represented by R⁴ refers to the alkenyl group having 2 to 6 of carbon atom and is preferably a vinyl group or a prop-1-en-2-yl group.

In Formula (I), the “alkoxy group having 1 to 6 of carbon atom” represented by R⁴ refers to the alkoxy group having 1 to 6 of carbon atom described above and is preferably a methoxy group.

In Formula (I), the “mono- or di-alkylamino group” in the “optionally substituted mono- or di-alkylamino group” represented by R⁵ refers to the mono- or dialkylamino group described above, and is preferably a mono- or di-(C1-C6 alkyl) amino group. Examples of the “substituent(s)” in the “optionally substituted mono- or di-alkylamino group” represented by R⁵ include the substituents described above.

R⁵ is more preferably an amino group, a hydroxylamino group, or a mono- or di-(C1-C6 alkyl)amino group, and particularly preferably an amino group.

In Formula (I), the “alkyl group having 1 to 6 of carbon atom” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R⁶ or R⁷ refers to the alkyl group having 1 to 6 of carbon atom described above, and is preferably an ethyl group, an n-propyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a pentyl group. Examples of the “substituent(s)” in the “optionally substituted alkyl group having 1 to 6 of carbon atom” represented by R⁶ or R⁷ include the substituents described above. The “substituent(s)” are preferably a hydroxyl group, cycloalkyl groups having 3 to 7 of carbon atom (for example, a cyclohexyl group), saturated heterocyclic groups (for example, a pyrrolidyl group and a morpholino group), unsaturated heterocyclic groups (for example, a pyridyl group), mono- or di-(C1-C6 alkyl)amino groups (for example, an ethylamino group and a dimethylamino group), (C1-C6 alkyl)thio groups (for example, a methylthio group), or alkoxy groups having 1 to 6 of carbon atom which optionally has a hydroxyl group.

In Formula (I), the “halogenoalkyl group having 1 to 6 of carbon atom” represented by R⁶ or R⁷ refers to the halogenoalkyl group having 1 to 6 of carbon atom described above, and is preferably a 2,2-difluoroethyl group or a 2,2,2-trifluoroethyl group.

In Formula (I), examples of the “cycloalkyl group having 3 to 7 of carbon atom” in the “optionally substituted cycloalkyl group having 3 to 7 of carbon atom” represented by R⁶ or R⁷ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group, and cycloalkyl group having 3 to 7 of carbon atom is preferably a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group. Examples of the “substituent(s)” in the “optionally substituted cycloalkyl group having 3 to 7 of carbon atom” represented by R⁶ or R⁷ include the substituents described above. The substituent(s) are preferably a hydroxyl group, an amino group, an amino acid-derived acyloxy group, an alkanoylamino group, or an alkylsulfonylamino group.

In Formula (I), the “aralkyl group” in the “optionally substituted aralkyl group” represented by R⁶ or R⁷ refers to the aralkyl group described above, and is preferably an aralkyl group having 7 to 12 of carbon atom, specifically, a benzyl group. Examples of the “substituent(s)” in the “optionally substituted aralkyl group” represented by R⁶ or R⁷ include the substituents described above. Specific examples of the substituent(s) include saturated heterocyclic groups such as a pyrrolidinyl group.

In Formula (I), the “aromatic hydrocarbon group” in the “optionally substituted aromatic hydrocarbon group” represented by R⁶ or R⁷ refers to the aromatic hydrocarbon group having 6 to 14 of carbon atom described above, and is preferably a phenyl group. Examples of the “substituent(s)” in the “optionally substituted aromatic hydrocarbon group” represented by R⁶ or R⁷ include the substituents described above. The substituent(s) are preferably halogen atoms, alkylthio groups (for example, a methylthio group), saturated heterocyclic groups (for example, a morpholino group), or substituted carbamoyl groups (for example, a pyrrolidine-carbonyl group).

In the Formula (I), the “saturated heterocyclic group” in the “optionally substituted saturated heterocyclic group” represented by R⁶ or R⁷ refers to the saturated heterocyclic group described above, and is preferably a piperidinyl group or a tetrahydropyranyl group. Examples of the “substituent(s)” in the “optionally substituted unsaturated heterocyclic group” represented by R⁶ or R⁷ include the substituents described above. The substituent(s) are preferably alkyl groups having 1 to 6 of carbon atom (for example, a methyl group), acyl groups (for example, an acetyl group), carbonyl groups having a saturated heterocyclic group (for example, a 2,6-dihydroxypyrimidinyl-4-carbonyl group), or aminoalkylcarbonyl groups (for example, a 2-aminoacetyl group).

In Formula (I), the “unsaturated heterocyclic group” in the “optionally substituted unsaturated heterocyclic group” represented by R⁶ or R⁷ refers to the unsaturated heterocyclic group described above, and is preferably a pyridyl group or an oxazolyl group. Examples of the “substituent(s)” in the “optionally substituted unsaturated heterocyclic group” represented by R⁶ or R⁷ include the substituents described above.

In Formula (I), the “saturated heterocyclic group” which is optionally formed by R⁶ and R⁷ together with the nitrogen atom to which they are bonded refers to a mono- or bi-cyclic saturated heterocyclic group preferably having 1 to 4 of any atom of an oxygen atom, a nitrogen atom, and a sulfur atom, and for example, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperazinyl group, a tetrahydrofuranyl group, or tetrahydropyranyl group.

In Formula (I), it is preferred for the combination of R⁶ and R⁷ that R⁶ be a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom; and R⁷ represent a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ optionally form a 5- to 7-membered saturated heterocyclic group, together with the nitrogen atom to which they are bonded. More preferably, R⁶ is a hydrogen atom, and R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, or an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O. Particularly preferably, R⁶ is a hydrogen atom, and R⁷ is an optionally substituted alkyl group having 1 to 6 of carbon atom or an optionally substituted cycloalkyl group having 3 to 7 of carbon atom.

In Formula (I), the “cycloalkyl group having 3 to 7 of carbon atom” in the “optionally substituted cycloalkyl group having 3 to 7 of carbon atom” represented by R⁸ refers to the cycloalkyl group having 3 to 7 of carbon atom described above, and is preferably a cyclohexyl group. Examples of the “substituent(s)” in the “optionally substituted cycloalkyl group having 3 to 7 of carbon atom” represented by R⁸ include the substituents described above. The substituent(s) are preferably a hydroxyl group.

In Formula (I), the “aromatic hydrocarbon group” in the “optionally substituted aromatic hydrocarbon group” represented by R⁸ refers to the aromatic hydrocarbon group having 6 to 14 of carbon atom described above, and is preferably a phenyl group. Examples of the “substituent(s)” in the “optionally substituted aromatic hydrocarbon group” represented by R⁸ include the substituents described above. The substituent(s) are preferably a hydroxyl group.

R⁸ is preferably an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom.

In Formula (I), the “mono- or di-alkylamino group” in the “optionally substituted mono- or di-alkylamino group” represented by R⁹ refers to the mono- or dialkylamino group described above, and is preferably a mono- or di-(C1-C6 alkyl)amino group. Examples of the “substituent(s)” in the “optionally substituted mono- or di-alkylamino group” represented by R⁹ include the substituents described above.

R⁹ is preferably a hydrogen atom, a hydroxyl group, an amino group or a mono- or di-(C1-C6 alkyl)amino group, and particularly preferably a hydrogen atom.

The preferred azabicyclo compound of the invention is a compound of Formula (I), in which X¹ is CH or N; X² is N and X³ and X⁴ are CH; Y¹ and Y³ are CH, any one or two of Y² and Y⁴ are C—R⁴, and the other is CH; R¹ is any of an optionally substituted 1H-imidazol-1-yl group, an optionally substituted pyrazol-4-yl group, an optionally substituted thiophen-3-yl group, an optionally substituted furan-2-yl group, an optionally substituted pyridin-3-yl group, an optionally substituted pyridin-4-yl group, an optionally substituted indol-5-yl group, an optionally substituted 1H-pyrrolo[2,3-b]pyridin-5-yl group, an optionally substituted benzofuran-2-yl group, an optionally substituted quinolin-3-yl group, and an optionally substituted 5,6,7,8-tetrahydroquinolin-3-yl group; R² is an alkyl group having 1 to 6 of carbon atom optionally having a halogen atom or an alkenyl group having 2 to 6 of carbon atom; R³ is —CO—R⁵; R⁴ is a halogen atom, an alkyl group having 1 to 6 of carbon atom optionally having a mono- or di-(C1-C6 alkyl)amino group or a monocyclic 5- to 7-membered saturated heterocyclic group having one or two of any heteroatom of N, S, and O, an alkoxy group having 1 to 6 of carbon atom, —N(R⁶) (R⁷), —SR⁸, or —CO—R⁹; R⁵ is an amino group or mono- or di-(C1-C6 alkyl)amino group; R⁶ is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 of carbon atom; R⁷ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 of carbon atom, an optionally substituted cycloalkyl group having 3 to 7 of carbon atom, an optionally substituted aralkyl group having 7 to 12 of carbon atom, an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom, an optionally substituted mono- or bi-cyclic saturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or an optionally substituted mono- or bi-cyclic unsaturated heterocyclic group having 1 to 4 of heteroatom selected from the group consisting of N, S, and O, or R⁶ and R⁷ form a 5- to 7-membered saturated heterocyclic group together with a nitrogen atom to which they are bonded; R⁸ is an optionally substituted cycloalkyl group having 3 to 7 of carbon atom or an optionally substituted aromatic hydrocarbon group having 6 to 14 of carbon atom; and R⁹ is a hydrogen atom, a hydroxyl group, an amino group, or a mono- or di-(C1-C6 alkyl)amino group.

More specifically, the azabicyclo compound is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (hereinafter, referred to as Compound 1).

The salt of the azabicyclo compound of the invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include acid addition salts of inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid) and organic acids (for example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, and glutamic acid); salts of inorganic bases (for example, sodium, potassium, magnesium, calcium, and aluminum), organic bases (for example, methylamine, ethylamine, meglumine, and ethanolamine), or a basic amino acids (for example, lysine, arginine, and ornithine); and ammonium salts.

Incidentally, the azabicyclo compound of the invention or a salt thereof can be synthesized according to the method described in WO 2011/004610 A, for example.

As described in Examples below, when the azabicyclo compound of the invention or a salt thereof is administered in combination with extremely various ranges of antitumor agents having different action mechanisms, the antitumor effect is synergistically potentiated. The “other antitumor agent” described in the invention is not particularly limited as long as it is a pharmaceutical having antitumor activity, and as the form thereof, any of a low molecular compound, an antibody, and a nucleic acid may be employed. Specific examples of antitumor agents exhibiting the synergic effect with the azabicyclo compound of the invention or a salt thereof include antitumor antibiotic substances such as amrubicin, doxorubicin, doxyl, epirubicin, and mitomycin C; alkylating agents such as cyclophosphamide and nimustine; platinum-based agents such as cisplatin, carboplatin, and oxaliplatin; pyrimidine-based antimetabolite agents such as 5-fluorouracil (5-FU), tegafur/gimeracil/oteracil potassium (TS-1, generic name “tegafur/gimeracil/oteracil potassium compounding agent” (trade name: “TS-1”)), tegafur/uracil (UFT, generic name “tegafur/uracil compounding agent” (trade name: “UFT”)), capecitabine, doxifluridine, 5-fluoro-2′-deoxyuridine (FdUrd), gemcitabine, and cytarabine; purine-based antimetabolite agents such as fludarabine, bendamustine, cladribine, and nelarabine; folic acid antimetabolite agents such as pemetrexed and methotrexate; plant alkaloid-based antitumor agents such as paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, irinotecan, and etoposide; immunomodulating drugs such as lenalidomide; low molecular weight molecular targeted drugs such as imatinib, gefitinib, dasatinib, erlotinib, lapatinib, everolimus, temsirolimus, bortezomib, crizotinib, vemurafenib, and ZD6244; and antibody molecular targeted drugs such as bevacizumab, trastuzumab, cetuximab, and rituximab. Among these, in terms of the synergic effect of antitumor effect in the case of concurrently using the azabicyclo compound of the invention or a salt thereof, one or more of agent selected from the group consisting of antitumor antibiotic substances, platinum-based agents, pyrimidine-based antimetabolite agents, purine-based antimetabolite agents, folic acid antimetabolite agents, plant alkaloid-based antitumor agents, immunomodulating drugs, and low molecular weight molecular targeted drugs are preferable.

As a specific antitumor agent, in terms of the synergic effect of antitumor effect in the case of concurrently using the azabicyclo compound of the invention or a salt thereof, one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, mitomycin C, cisplatin, oxaliplatin, 5-FU, TS-1, UFT, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, irinotecan, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, bortezomib, crizotinib, vemurafenib, and ZD6244 are preferable, one or more of kind(s) selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib are more preferable, and one or more of kind(s) selected from the group consisting of amrubicin, cisplatin, etoposide, gemcitabine, paclitaxel (for example, TAXOL or ABRAXANE), docetaxel, and crizotinib are particularly preferable.

Specific examples of a cancer to be treated by the antitumor agent of the invention include head and neck cancer, digestive organ cancer (for example, esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary tract cancer (for example, gallbladder/bile duct cancer), pancreatic cancer, small intestinal cancer, large intestine cancer (for example, colorectal cancer, colon cancer, or rectal cancer), lung cancer (for example, non-small cell lung cancer or small cell lung cancer), breast cancer, ovarian cancer, uterus cancer (for example, cervical cancer or uterine corpus cancer), kidney cancer, bladder cancer, prostate cancer, skin cancer (for example, malignant melanoma or epidermal cancer), and blood cancer (for example, multiple myeloma or acute myelocytic leukemia). Among these, in terms of the synergic effect of the antitumor effect when the azabicyclo compound of the invention or a salt thereof is used in combination with the antitumor agent, the cancer is preferably digestive organ cancer, lung cancer, breast cancer, skin cancer, or blood cancer, and more preferably colorectal cancer, lung cancer, breast cancer, gallbladder cancer, pancreatic cancer, stomach cancer, skin cancer, or blood cancer. Incidentally, herein, the cancer includes not only primary tumor but also cancer metastasizing to other organ(s) (for example, liver). In addition, the antitumor agent of the invention may be used for postoperative adjuvant chemotherapy which is performed for prevention of recurrence after a tumor is removed surgically or may be used for preoperative adjuvant chemotherapy which is preliminarily performed for removing surgically a tumor.

There is no particular limitation on the administration form of the antitumor agent of the invention, and appropriate form can be selected in accordance with the therapeutic purpose. Specific examples of the form of the antitumor agent include oral agents (for examples, tablets, coated tablets, powder, granules, capsules, and liquid), injections, suppositories, cataplasms, and ointments.

The administration schedule of the antitumor agent of the invention is appropriately selected in the range in which each active ingredient exerts the antitumor effect, and each active ingredient is administered simultaneously or separately at an interval.

The antitumor agent of the invention may be prepared in such a manner that respective active ingredients are separated into multiple dosage forms or are collectively prepared in one dosage form, on the basis of the administration forms or the administration schedules of the active ingredients. In addition, each drug formulation may be produced and sold in one package suitable for use at each event of combined administration or may be produced and sold in separate packages.

The antitumor agent in the invention can be prepared through a generally known method by use of a pharmacologically acceptable carrier, according to the administration form. Such a carrier can be selected from the group consisting of a variety of carriers generally employed in pharmaceuticals, and examples thereof can include an excipient, a binder, a disintegrant, a lubricant, a diluent, a solubilizing agent, a suspending agent, a tonicity agent, a pH-adjusting agent, a buffer, a stabilizer, a coloring agent, a flavoring agent, and a deodorant.

The invention also relates to an antitumor effect potentiator containing the azabicyclo compound of the invention or a salt thereof, which is used for potentiating the antitumor effect of other antitumor agent(s) with respect to a cancer patient. The antitumor effect potentiator has the formulation aspect of the antitumor agent described above.

The invention also relates to an antitumor agent containing the azabicyclo compound of the invention or a salt thereof, which is used for treating a cancer patient who has been administered other antitumor agent(s). The antitumor agent has the above-described formulation aspect.

The invention also relates to a kit preparation including directions for use in which the azabicyclo compound of the invention or a salt thereof and administration of the azabicyclo compound of the invention or a salt thereof in combination with other antitumor agent(s) to a cancer patient are described. Herein, the “directions for use” may be directions for use in which the above-described dosage is described. Although it does not matter whether the directions for use are legally bound or not, directions for use in which the above-described dosage is recommended are preferable. Specifically, a package insert or a pamphlet is exemplified. In addition, the kit preparation including directions for use may be a kit preparation in which directions for use are printed on or attached to the package of the kit preparation or a kit preparation in which directions for use are enclosed in the package of the kit preparation together with an antitumor agent.

EXAMPLES

Hereinafter, the invention will be described in more detail by means of Examples and Reference Examples.

Example 1

A combination of Compound 1 and docetaxel exhibits the potentiated antitumor activity with respect to a human tumor cell of nude mouse xenograft model having a non-small cell lung cancer (NSCLC) cell NCI-H2170.

NCI-H2170 (ATCC # CRL-5928) as a human non-small cell lung cancer (NSCLC) cell line was obtained from American Type Culture Collection (ATCC; Manassas, Va., USA). In RPMI-1640 (containing 4.5 g/L of glucose, 10 mM of HEPES, and 1 mM of sodium pyruvate) (Wako Pure Chemical Industries, Ltd.) medium supplemented with 10% fetal bovine serum (FBS), cell lines were cultured. The cells cryopreserved in liquid nitrogen were quickly thawed at 37° C., transferred to a tissue culture flask containing a medium, and allowed to grow in a 5% CO₂ incubator at 37° C. The NCI-H2170 cell lines were sub-cultured once to twice a week at a dilution ratio of 1:5 to 1:10. The cells which were grown to 80 to 90% confluence in a 75 cm² flask were washed with 10 mL of phosphate buffer saline (PBS), and 10 mL of 0.25% trypsin-EDTA was then added thereto, followed by incubation until the cells were separated from the surface of the flask. 10 mL of medium for inactivation of trypsin was added thereto, a cell suspension was collected, and after centrifugal separation, the cell pellet was re-suspended in 10 mL of growth medium and then seeded in a 175 cm² flask into which 30 mL of medium was put, followed by incubation in a 5% CO₂ incubator at 37° C. When the flask reached 80 to 90% confluence, the above-described sub-culturing was repeated until cells sufficient for transplantation into mice were obtained.

Five-week old BALB/cAJc1-nu/nu mice (nude mice) were obtained from CREA Japan, Inc. Animals were housed in 5 or 6 microisolator cages under a 12-hour light/12-hour dark cycle, acclimated at least one week before use, and appropriately fed with a usual feed. The animals at the time of transplantation were six- to eight-week old. In order to transplant NCI-H2170 cells to the nude mice, cells were collected as described above, washed in PBS, and re-suspended at a concentration of 5×10⁷ cell/mL in 50% PBS and 50% Matrigel basement membrane matrix (#356237; BD Biosciences; Bedford, Mass., USA). A 5×10⁶ cell/0.1 mL of cell suspension was transplanted subcutaneously to the right dorsal region of the nude mouse by using a 1 mL tuberculin syringe and a 25 G needle.

Subsequently, the cell was allowed to grow for one to two weeks after transplantation until the tumor volume (TV) reached 100 to 300 mm³. Digimatic Caliper was used in measurement of the tumor diameter, the major axis and the minor axis of the tumor were measured, and TV was calculated by the following formula. TV (mm³)=(Major axis×minor axis²)/2, units of the major axis and the minor axis: mm

Animals having an extremely small or large tumor volume were excluded and the remaining animals were allocated to each group by a stratified randomization allocation method using TV as an index. A relative tumor volume (RTV) was calculated from TV as an endpoint. In addition, a treatment/control (T/C) value (%) that is an RTV ratio of the RTV of the pharmaceutical administered group to the RTV of the control group on the end date of test period was calculated as an evaluation index. RTV and T/C (%) were calculated by the following formula. RTV=TV_(n)/TV₁ T/C (%)=(Average RTV of each pharmaceutical administered group on test end date)/(Average RTV of control group on test end date)×100

TV₁ represents the tumor volume of Day 1.

In order to administer Compound 1, a 0.5% hypromellose aqueous solution was prepared. Hypromellose was weighed in a beaker, and distilled water (Otsuka Pharmaceutical Factory, Inc.) was added thereto in an amount of about 80% of the preparation amount. The mixture was completely dissolved by being stirred overnight using a stirrer at a low-temperature chamber, the resultant solution was transferred to a measuring cylinder, and distilled water was added to dilute to the preparation amount. Compound 1 was weighed in a necessary amount, pulverized with an agate mortar, suspended with a 0.5% hypromellose aqueous solution to have a predetermined concentration, and then subjected to ultrasonic treatment, thereby obtaining a homogeneous suspension. 10 mL of this suspension was administered orally per kg of body weight. Incidentally, the suspension was stored in a refrigerator at times other than administration. This suspension is refrigerator-stable for two weeks.

As docetaxel, 80 mg of Taxotere (registered trademark) for intravenous drip infusion (Sanofi-Aventis SA) was dissolved according to the package insert, and was diluted with physiological saline so as to have a predetermined concentration immediately before administration. On the first day of administration, 5 mL of the prepared docetaxel was administered intravenously per kg of body weight.

Both the treatment with 5 mg/kg of body weight of Compound 1 and the treatment with 15 mg/kg of body weight of docetaxel slightly inhibited the growth of NCI-H2170 tumor in the nude mice, and the T/C values were 72 and 86, respectively. In contrast, the concomitant treatment with a combination of 5 mg/kg of body weight of Compound 1 and 15 mg/kg of body weight of docetaxel further inhibited the growth of NCI-H2170 tumor in the nude mice, and the T/C value was 43. Further, the treatment with one of 10 mg/kg of body weight of Compound 1 and 30 mg/kg of body weight of docetaxel or a combination thereof were carried out. However, the effect observed in each concomitant treatment group was potentiated more significantly (P<0.05; Intersection-Union test) compared to the effect observed in the group treated only with any one of pharmaceuticals. The results thereof are shown in FIG. 1. Regarding the average body weight change on the end date of test period, all of the groups treated with the combination of Compound 1 and docetaxel were accompanied with no toxicity with respect to the control group.

Example 2

A combination of Compound 1 and paclitaxel exhibits the potentiated antitumor activity with respect to a human tumor cell of nude mouse xenograft model having NSCLC NCI-H441 cells.

An NCI-H441 cell (ATCC # HTB-174) was transplanted to nude mice according to the description in Example 1. The cell was allowed to grow for one week after transplantation until the large majority of tumors reached 100 to 300 mm³.

In order to administer paclitaxel, paclitaxel was weighed in a necessary amount, ethanol (NACALAI TESQUE, INC.) was added thereto in an amount of 10% of the preparation amount, and the mixture was dissolved by ultrasonic treatment. Next, Cremophor EL (NACALAI TESQUE, INC.) was added thereto in the same amount as ethanol, and the mixture was dissolved by ultrasonic treatment. Physiological saline was added and mixed in an amount of 10% of the preparation amount immediately before administration, thereby preparing a paclitaxel administration solution. On the first day of administration, 5 mL of the paclitaxel administration solution was administered intravenously per kg of body weight.

As shown in FIG. 2, both the treatment with 5 mg/kg of body weight of Compound 1 and the treatment with 30 mg/kg of body weight of paclitaxel inhibited the growth of NCI-H441 tumor in the nude mice, and the T/C values were 63 and 41, respectively. In contrast, in the case of concomitant treatment with these pharmaceuticals, the inhibitory effect of NCI-H441 tumor growth in the nude mice was potentiated and the T/C value was 28. Further, the treatment with 15 mg/kg of body weight or 60 mg/kg of body weight of docetaxel alone and the concomitant treatment with docetaxel and 5 mg/kg of body weight of Compound 1 were carried out. However, the effect observed in each concomitant treatment group was potentiated more significantly (P<0.05; Intersection-Union test) compared to the effect observed in the group treated only with any one of pharmaceuticals. Regarding the toxicity using the body weight change on the end date of test period as an index, the group treated with the combination of Compound 1 and paclitaxel was well in the tolerable range with respect to the control group. In addition, the same result was also obtained in the stomach cancer line.

Example 3

A combination of Compound 1 and cisplatin exhibits the potentiated antitumor activity with respect to a human tumor cell of nude mouse xenograft model having a stomach cancer line NCI-N87 cell.

An NCI-N87 cell (ATCC # CRL-5822) was transplanted to nude mice according to the description in Example 1. The cell was allowed to grow for one week after transplantation until the large majority of tumors reached 100 to 300 mm³.

As cisplatin, 25 mg of Briplatin for injection (Bristol-Myers Squibb Company) was dissolved according to the package insert, and was diluted with physiological saline so as to have a predetermined concentration immediately before administration. On the first day of administration, 14.0 mL of the prepared cisplatin was administered intravenously per kg of body weight.

As shown in FIG. 3, both the treatment with 5 mg/kg of body weight of Compound 1 and the treatment with 7 mg/kg of body weight of cisplatin inhibited the growth of NCI-N87 tumor in the nude mice, and the T/C values were 51 and 65, respectively. In contrast, in the case of concomitant treatment with these pharmaceuticals, the inhibitory effect of NCI-N87 tumor growth in the nude mice was potentiated and the T/C value was 26. Further, the treatment with 10 mg/kg of body weight or 20 mg/kg of body weight of Compound 1 alone and the concomitant treatment with Compound 1 and 7 mg/kg of body weight of cisplatin were carried out. However, the effect observed in each concomitant treatment group was potentiated more significantly (P<0.05; Intersection-Union test) compared to the effect observed in the group treated only with any one of pharmaceuticals. Regarding the toxicity using the body weight change on the end date of test period as an index, the group treated with the combination of Compound 1 and cisplatin was well in the tolerable range with respect to the control group.

Example 4

A combination of Compound 1 and amrubicin exhibits the potentiated antitumor activity with respect to a human tumor cell of nude mouse xenograft model having a small cell lung cancer line SBC-1 cell.

An SBC-1 cell (purchased from Health Science Research Resources Bank, # JCRB0816) was transplanted to nude mice according to the description in Example 1. The cell was allowed to grow for one week after transplantation until the large majority of tumors reached 100 to 300 mm³.

As amrubicin, 20 mg of Calsed (registered trademark) for injection (Sumitomo Dainippon Pharma Co., Ltd.) was dissolved according to the package insert, and was diluted with physiological saline so as to have a predetermined concentration immediately before administration. On the first day of administration, 10.0 mL of the prepared amrubicin was administered intravenously per kg of body weight.

On Days 1, 3, 5, 8, 10, and 12, 10.0 mL of Compound 1 was administered orally per kg of body weight.

As shown in FIG. 4, both the treatment with 28 mg/kg of body weight of Compound 1 and the treatment with 12.5 mg/kg of body weight of amrubicin inhibited the growth of SBC-1 tumor in the nude mice, and the T/C values were 49 and 40, respectively. In contrast, in the case of concomitant treatment with these pharmaceuticals, the inhibitory effect of SBC-1 tumor growth in the nude mice was potentiated and the T/C value was 17. Further, the treatment with 20 mg/kg of body weight of Compound 1 alone and the concomitant treatment with Compound 1 and 12.5 mg/kg of body weight of amrubicin were carried out. However, the effect observed in each concomitant treatment group was potentiated more significantly (P<0.05; Intersection-Union test) compared to the effect observed in the group treated only with any one of pharmaceuticals. Regarding the toxicity using the body weight change on the end date of test period as an index, the group treated with the combination of Compound 1 and amrubicin was well in the tolerable range with respect to the control group.

Example 5: In Vitro Combination Analysis of Compound 1 and Crizotinib

A. Material and Method

In RPMI-1640 medium (Wako Pure Chemical Industries, Ltd.) supplemented with 10% fetal bovine serum (Thermo Scientific), human stomach cancer cell lines NUGC-4 and MKN45 (Health Science Research Resources Bank, HSRRB) were allowed to grow. All of the cells were maintained at 37° C. and 5% CO₂, and sub-cultured once to twice a week at a dilution ratio of 1:5 to 1:20.

Cell Survival Assay

The cell survival rate was measured using CellTiter-Glo. The cells were recovered by a general method, suspended in RPMI-1640 medium supplemented with 10% fetal bovine serum and antibiotic substances (penicillin and streptomycin), and seeded in a 384-well plate. The number of cells to be seeded was set to 500 cell/20 μL per well. The seeded cells were incubated at 37° C. and 5% CO₂ for 24 hours, and then 5 μL of a medium supplemented with crizotinib and Compound 1 or Vehicle (DMSO) was added thereto. As crizotinib, nine of a 3-fold dilution series from 10 μM and zero concentration (DMSO) were used, and as Compound 1, seven of 3-fold dilution series from 10 μM and zero concentration (DMSO) were used. All of 80 combinations thereof were examined. With respect to each combination, four wells were allocated. Further, incubation was carried out at 37° C. and 5% CO₂ for 72 hours. 25 μL of CellTiter-Glo liquid per well was added, and then incubation was carried out at room temperature for 10 minutes. The chemiluminescence was measured by Envision as a plate reader. The average value of four wells of each combination was calculated from the obtained data, and the standardized cell survival rate was calculated with respect to the control added with a medium supplemented with Vehicle. The Fa (Fraction of Affect) was calculated by subtracting the cell survival rate from 1.

The half inhibition concentration (IC50) of each pharmaceutical was determined using median effect analysis software CalcuSyn 2.0 (CalcuSyn, Inc.). Subsequently, the combination index (CI) of each combination concentration of pharmaceuticals was determined. The CI values of more than 1, equal to 1, and less than 1 each indicate antagonistic effect, additive effect, and synergic effect (Table 1) (Pharmacol Rev. 2006; 58(3):621-81, BMC Complement Altern Med. 2013; 13:212, Anticancer Res. 2005; 25(3B):1909-17).

TABLE 1 (Explanation of combination index value) Range of CI (upper limit) Explanation 0.1 Extremely strong synergic effect 0.3 Strong synergic effect 0.7 Synergic effect 0.85 Moderate synergic effect 0.9 Slight synergic effect 1 Substantially additive 1.2 Modest antagonistic effect 1.45 Moderate antagonistic effect 3.3 Antagonistic effect 10 Strong antagonistic effect >10 Extremely strong antagonistic effect

Further, the Fa value close to 1 is considered to be a concentration range in which the effect of one of pharmaceuticals is too strong, and the Fa value close to 0 is considered to be a concentration range in which the effect of one of pharmaceuticals is too weak. These values are not suitable for discussion on the synergistic effect. Therefore, the concentration combination of both the pharmaceuticals satisfying 0.2≤Fa≤0.8 was extracted from the Fa values calculated by 80 concentration combinations of Compound 1 and crizotinib in total in the NUGC-4 cell, and the extracted concentration combination is used in the linear curve fitting by CalcuSyn to obtain a CI.

B. Result

The obtained CI and the concentrations of both pharmaceuticals applied therewith were examined and the concentration range of each of both the pharmaceuticals in which the CI became moderate degree or higher synergic effect (less than 0.85) was found (Table 2).

TABLE 2 Compound 1 Crizotinib Concomitant (nM) (nM) Fa CI ratio 13.7174 4.57247 0.34 0.291 Strong 1:0.33333 synergic effect 13.7174 13.7174 0.527 0.139 Strong 1:1     synergic effect 13.7174 41.1523 0.53 0.383 Synergic effect 1:3.00001 41.1523 4.57247 0.339 0.368 Synergic effect 1:0.11111 41.1523 13.7174 0.579 0.103 Strong 1:0.33333 synergic effect 41.1523 41.1523 0.534 0.391 Synergic effect 1:1     41.1523 123.457 0.567 0.816 Moderate 1:3     synergic effect 123.457 1.52416 0.289 0.622 Synergic effect 1:0.01235 123.457 4.57247 0.417 0.319 Synergic effect 1:0.03704 123.457 13.7174 0.581 0.149 Strong 1:0.11111 synergic effect 123.457 41.1523 0.582 0.3 Synergic effect 1:0.33333 370.37 1.52416 0.645 0.148 Strong 1:0.00412 synergic effect 370.37 4.57247 0.624 0.182 Strong 1:0.01235 synergic effect 370.37 13.7174 0.631 0.205 Strong 1:0.03704 synergic effect 370.37 41.1523 0.64 0.278 Strong 1:0.11111 synergic effect 370.37 123.457 0.66 0.446 Synergic effect 1:0.33333 1111.11 1.52416 0.75 0.201 Strong 1:0.00137 synergic effect 1111.11 4.57247 0.74 0.221 Strong 1:0.00412 synergic effect 1111.11 13.7174 0.742 0.227 Strong 1:0.01235 synergic effect 1111.11 41.1523 0.739 0.262 Strong 1:0.03704 synergic effect 1111.11 123.457 0.722 0.41 Synergic effect 1:0.11111 3333.33 41.1523 0.717 0.833 Moderate 1:0.01235 synergic effect

In the concentration range from 13.7174 nM to 1111.11 nM of Compound 1 and the concentration range from 4.57247 nM to 41.1523 nM of crizotinib in the NUGC-4 cell, a large number of combinations exhibiting a strong synergic effect were found. This means that in these concentration ranges, cell death was induced greater than expected from the additive effect of dosage of respective pharmaceuticals.

In addition, similarly to the result of the NUGC-4 cell described above, regarding the MKN45 cell, when the incubation was carried out for 72 hours while Compound 1 and crizotinib were simultaneously added, a large number of combinations exhibiting a strong synergic effect also were found in the concentration range from 13.7174 nM to 370.37 nM of Compound 1 and the concentration range from 13.7174 nM to 123.457 nM of crizotinib (Table 3).

TABLE 3 Compound 1 Crizotinib Concomitant (nM) (nM) Fa CI ratio 13.7174 41.1523 0.796 0.048 Extremely strong 1:3.00001 synergic effect 13.7174 370.37 0.795 0.418 Synergic effect  1:27.00001 41.1523 13.7174 0.346 0.772 Moderate 1:0.33333 synergic effect 41.1523 41.1523 0.792 0.056 Extremely strong 1:1     synergic effect 123.457 13.7174 0.395 0.709 Moderate 1:0.11111 synergic effect 370.37 1.52416 0.562 0.34 Synergic effect 1:0.00412 370.37 4.57247 0.562 0.367 Synergic effect 1:0.01235 370.37 13.7174 0.727 0.153 Strong 1:0.03704 synergic effect 370.37 41.1523 0.792 0.123 Strong 1:0.11111 synergic effect 370.37 123.457 0.796 0.21 Strong 1:0.33333 synergic effect 370.37 370.37 0.78 0.575 Synergic effect 1:1     1111.11 1.52416 0.733 0.354 Synergic effect 1:0.00137 1111.11 4.57247 0.74 0.344 Synergic effect 1:0.00412 1111.11 13.7174 0.723 0.408 Synergic effect 1:0.01235 1111.11 41.1523 0.769 0.332 Synergic effect 1:0.03704 1111.11 123.457 0.753 0.523 Synergic effect 1:0.11111 3333.33 1.52416 0.764 0.846 Moderate 1:0.00046 synergic effect 3333.33 4.57247 0.77 0.813 Moderate 1:0.00137 synergic effect 3333.33 41.1523 0.776 0.827 Moderate 1:0.01235 synergic effect

Example 6: In Vitro Combination Analysis of Compound 1 and Other Antitumor Agents

The same in vitro combination analysis was also performed on a combination of Compound 1 and other antitumor agents with respect to a cell line other than those described above. All of the antitumor agents presented in Table 4 to Table 39 exhibited moderate degree or higher synergic effect with Compound 1 (CI<0.85). Particularly, in imatinib, etoposide, erlotinib, oxaliplatin, gefitinib, gemcitabine, cisplatin, cytarabine, dasatinib, doxorubicin, docetaxel, paclitaxel, pemetrexed, lapatinib, and lenalidomide, a strong synergic effect (CI<0.30) exhibited in one or more of concentration combination.

TABLE 4 <Antitumor agent: 5-FU,Cancer type: epidermal cancer, Cell line: A431> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 5555.56 0.563 0.475 Synergic effect  1:405.00095 41.1523 5555.56 0.537 0.613 Synergic effect  1:134.99999 3333.33 7.62079 0.676 0.804 Moderate 1:0.00229 synergic effect 3333.33 22.8624 0.678 0.797 Moderate 1:0.00686 synergic effect 3333.33 68.5871 0.698 0.726 Moderate 1:0.02058 synergic effect 3333.33 205.761 0.688 0.765 Moderate 1:0.06173 synergic effect 3333.33 617.284 0.701 0.728 Moderate 1:0.18519 synergic effect 3333.33 1851.85 0.716 0.698 Synergic effect 1:0.55556 3333.33 5555.56 0.712 0.786 Moderate 1:1.66667 synergic effect

TABLE 5 <Antitumor agent: ZD6244, Cancer type: malignant melanoma, Cell line: A375> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 41.1523 0.252 0.55 Synergic effect 1:3.00001 13.7174 123.457 0.479 0.314 Synergic effect 1:9.00003 13.7174 370.37 0.59 0.442 Synergic effect  1:27.00001 13.7174 1111.11 0.68 0.692 Synergic effect  1:81.00004 41.1523 123.457 0.447 0.415 Synergic effect 1:3     41.1523 370.37 0.577 0.501 Synergic effect 1:8.99998 41.1523 1111.11 0.685 0.679 Synergic effect  1:26.99995 123.457 123.457 0.432 0.546 Synergic effect 1:1     123.457 370.37 0.572 0.576 Synergic effect 1:2.99999 123.457 1111.11 0.681 0.741 Moderate 1:8.99998 synergic effect 370.37 41.1523 0.352 0.758 Moderate 1:0.11111 synergic effect 370.37 123.457 0.443 0.772 Moderate 1:0.33333 synergic effect 370.37 370.37 0.606 0.624 Synergic effect 1:1     370.37 1111.11 0.69 0.813 Moderate 1:3     synergic effect 1111.11 41.1523 0.61 0.741 Moderate 1:0.03704 synergic effect 1111.11 123.457 0.68 0.63 Synergic effect 1:0.11111 1111.11 370.37 0.753 0.547 Synergic effect 1:0.33333 1111.11 1111.11 0.769 0.722 Moderate 1:1     synergic effect

TABLE 6 <Antitumor agent: SM-38, Cancer type: epidermal cancer, Cell line: A431> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 13.7174 0.584 0.437 Synergic effect 1:1     41.1523 13.7174 0.514 0.652 Synergic effect 1:0.33333 41.1523 41.1523 0.773 0.384 Synergic effect 1:1     123.457 41.1523 0.719 0.578 Synergic effect 1:0.33333 3333.33 1.52416 0.557 0.584 Synergic effect 1:0.00046 3333.33 4.57247 0.558 0.694 Synergic effect 1:0.00137 3333.33 13.7174 0.611 0.807 Moderate 1:0.00412 synergic effect 3333.33 41.1523 0.785 0.556 Synergic effect 1:0.01235

TABLE 7 <Antitumor agent: imatinib, Cancer type: acute myelocytic leukemia, Cell line: Kasumi-1> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 370.37 0.327 0.566 Synergic effect  1:27.00001 13.7174 1111.11 0.488 0.272 Strong  1:81.00004 synergic effect 13.7174 3333.33 0.51 0.595 Synergic effect  1:243.00013 41.1523 370.37 0.369 0.446 Synergic effect 1:8.99998 41.1523 1111.11 0.52 0.256 Strong  1:26.99995 synergic effect 41.1523 3333.33 0.55 0.443 Synergic effect  1:80.99985 123.457 370.37 0.409 0.561 Synergic effect 1:2.99999 123.457 1111.11 0.564 0.335 Synergic effect 1:8.99998 123.457 3333.33 0.556 0.576 Synergic effect  1:26.99993 370.37 4.57247 0.616 0.592 Synergic effect 1:0.01235 370.37 13.7174 0.621 0.583 Synergic effect 1:0.03704 370.37 41.1523 0.576 0.673 Synergic effect 1:0.11111 370.37 123.457 0.599 0.631 Synergic effect 1:0.33333 370.37 370.37 0.632 0.578 Synergic effect 1:1     370.37 1111.11 0.694 0.48 Synergic effect 1:3     370.37 3333.33 0.697 0.516 Synergic effect 1:9     370.37 30000 0.737 0.722 Moderate  1:81.00008 synergic effect

TABLE 8 <Antitumor agent: etoposide, Cancer type: large intestine cancer, Cell line: HCT-116> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 1111.11 0.421 0.772 Moderate  1:81.00004 synergic effect 41.1523 3333.33 0.638 0.741 Moderate  1:80.99985 synergic effect 123.457 1111.11 0.495 0.638 Synergic effect 1:8.99998 123.457 3333.33 0.655 0.723 Moderate  1:26.99993 synergic effect 370.37 3333.33 0.71 0.648 Synergic effect 1:9     1111.11 1.52416 0.637 0.716 Moderate 1:0.00137 synergic effect 1111.11 4.57247 0.64 0.709 Moderate 1:0.00412 synergic effect 1111.11 13.7174 0.623 0.754 Moderate 1:0.01235 synergic effect 1111.11 41.1523 0.638 0.722 Moderate 1:0.03704 synergic effect 1111.11 123.457 0.671 0.655 Synergic effect 1:0.11111 1111.11 370.37 0.685 0.662 Synergic effect 1:0.33333 1111.11 1111.11 0.714 0.689 Synergic effect 1:1     1111.11 3333.33 0.753 0.808 Moderate 1:3     synergic effect

TABLE 9 <Antitumor agent: etoposide, Cancer type: epidermal cancer, Cell line: A431> Compound 1 Antitumor Concomitant (nM) agent (nM) Fa CI CI_COMMENT ratio 13.7174 3333.33 0.279 0.29 Strong  1:243.00013 synergic effect 13.7174 10000 0.624 0.037 Extremely strong  1:729.00112 synergic effect 41.1523 10000 0.672 0.028 Extremely strong  1:242.99978 synergic effect 123.457 3333.33 0.23 0.649 Synergic effect 1:26.99993 123.457 10000 0.616 0.061 Extremely strong 1:80.99986 synergic effect 370.37 10000 0.587 0.132 Strong 1:27.00003 synergic effect 1111.11 10000 0.472 0.555 Synergic effect 1:9.00001  10000 3333.33 0.782 0.79 Moderate 1:0.33333  synergic effect 10000 10000 0.783 0.789 Moderate 1:1     synergic effect

TABLE 10 <Antitumor agent: erlotinib, Cancer type: non- small cell lung cancer, Cell line: A549> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 370.37 0.275 0.572 Synergic effect  1:27 13.7174 1111.11 0.377 0.715 Moderate  1:81 synergic effect 13.7174 10000 0.695 0.611 Synergic effect  1:729 41.1523 123.457 0.275 0.36 Synergic effect 1:3 41.1523 370.37 0.345 0.426 Synergic effect 1:9 41.1523 1111.11 0.386 0.749 Moderate  1:27 synergic effect 41.1523 3333.33 0.516 0.825 Moderate  1:81 synergic effect 41.1523 10000 0.729 0.479 Synergic effect  1:243 123.457 123.457 0.281 0.716 Moderate 1:1 synergic effect 123.457 370.37 0.359 0.653 Synergic effect 1:3 123.457 10000 0.72 0.58 Synergic effect  1:81 370.37 1.52416 0.558 0.554 Synergic effect 1:0 370.37 4.57247 0.581 0.508 Synergic effect   1:0.01 370.37 13.7174 0.549 0.576 Synergic effect   1:0.04 370.37 41.1523 0.579 0.517 Synergic effect   1:0.11 370.37 123.457 0.683 0.344 Synergic effect   1:0.33 370.37 370.37 0.718 0.305 Synergic effect 1:1 370.37 1111.11 0.772 0.253 Strong 1:3 synergic effect 1111.11 13.7174 0.795 0.58 Synergic effect   1:0.01

TABLE 11 <Antitumor agent: oxaliplatin, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 3333.33 0.489 0.562 Synergic effect  1:243.00013 13.7174 10000 0.784 0.104 Strong  1:729.00112 synergic effect 41.1523 3333.33 0.488 0.604 Synergic effect  1:80.99985 41.1523 10000 0.777 0.129 Strong  1:242.99978 synergic effect 123.457 3333.33 0.498 0.666 synergic effect  1:26.99993 123.457 10000 0.79 0.158 Strong  1:80.99986 synergic effect 370.37 1.52416 0.461 0.539 Synergic effect 1:0.00412 370.37 4.57247 0.484 0.508 Synergic effect 1:0.01235 370.37 13.7174 0.463 0.538 Synergic effect 1:0.03704 370.37 41.1523 0.483 0.516 Synergic effect 1:0.11111 370.37 123.457 0.509 0.493 Synergic effect 1:0.33333 370.37 370.37 0.558 0.453 Synergic effect 1:1     370.37 1111.11 0.604 0.439 Synergic effect 1:3     370.37 3333.33 0.771 0.261 Strong 1:9     synergic effect

TABLE 12 <Antitumor agent: gefitinib, Cancer type: non- small cell lung cancer, Cell line: HCC827> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 2.28624 0.215 0.66 Synergic effect 1:0.16667 13.7174 6.85871 0.477 0.262 Strong 1:0.5   synergic effect 13.7174 20.5761 0.739 0.125 Strong 1:1.5   synergic effect 41.1523 6.85871 0.442 0.382 Synergic effect 1:0.16667 41.1523 20.5761 0.721 0.154 Strong 1:0.5   synergic effect 41.1523 61.7284 0.798 0.223 Strong 1:1.5   synergic effect 123.457 20.5761 0.68 0.248 Strong 1:0.16667 synergic effect 123.457 61.7284 0.751 0.364 Synergic effect 1:0.5   123.457 185.185 0.797 0.676 Synergic effect 1:1.5   370.37 20.5761 0.598 0.63 Synergic effect 1:0.05556 370.37 61.7284 0.662 0.846 Moderate 1:0.16667 synergic effect 1111.11 0.762079 0.75 0.321 Synergic effect 1:0.00069 1111.11 2.28624 0.749 0.332 Synergic effect 1:0.00206 1111.11 6.85871 0.753 0.346 Synergic effect 1:0.00617 1111.11 20.5761 0.776 0.345 Synergic effect 1:0.01852 1111.11 61.7284 0.774 0.53 Synergic effect 1:0.05556 3333.33 2.28624 0.796 0.654 Synergic effect 1:0.00069 3333.33 6.85871 0.787 0.726 Moderate 1:0.00206 synergic effect 3333.33 20.5761 0.799 0.699 Synergic effect 1:0.00617

TABLE 13 <Antitumor agent: gemcitabine, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 13.7174 0.767 0.038 Extremely strong 1:1     synergic effect 41.1523 13.7174 0.697 0.111 Strong 1:0.33333 synergic effect 123.457 13.7174 0.736 0.103 Strong 1:0.11111 synergic effect 370.37 13.7174 0.598 0.585 Synergic effect 1:0.03704 370.37 123.457 0.75 0.528 Synergic effect 1:0.33333 1111.11 4.57247 0.675 0.641 Synergic effect 1:0.00412 1111.11 13.7174 0.783 0.369 Synergic effect 1:0.01235 1111.11 41.1523 0.773 0.455 Synergic effect 1:0.03704 1111.11 123.457 0.762 0.713 Moderate 1:0.11111 synergic effect

TABLE 14 <Antitumor agent: gemcitabine, Cancer type: gallbladder cancer, Cell line: TGBC2TKB> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 500.0 62.5 0.660 0.371 Synergic effect 1:0.13 500.0 125.0 0.708 0.365 Synergic effect 1:0.25 500.0 250.0 0.721 0.450 Synergic effect 1:0.5  500.0 500.0 0.715 0.682 Synergic effect 1:1   1000.0 62.5 0.652 0.686 Synergic effect 1:0.06 1000.0 125.0 0.695 0.649 Synergic effect 1:0.13 1000.0 250.0 0.700 0.756 Moderate 1:0.25 synergic effect

TABLE 15 <Antitumor agent: gemcitabine, Cancer type: non- small cell lung cancer, Cell line: NCI-H522> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 1250 200 0.391 0.723 Moderate 1:0.16 synergic effect 1250 400 0.470 0.595 Synergic effect 1:0.32 1250 800 0.567 0.490 Synergic effect 1:0.64 2500 200 0.527 0.435 Synergic effect 1:0.08 2500 400 0.602 0.329 Synergic effect 1:0.16 2500 800 0.594 0.502 Synergic effect 1:0.32 5000 200 0.578 0.522 Synergic effect 1:0.04 5000 400 0.644 0.376 Synergic effect 1:0.08 5000 800 0.627 0.548 Synergic effect 1:0.16 10000 200 0.618 0.718 Moderate 1:0.02 synergic effect 10000 400 0.638 0.675 Synergic effect 1:0.04

TABLE 16 <Antitumor agent: gemcitabine, Cancer type: epidermal cancer, Cell line: A431> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 123.457 0.649 0.429 Synergic effect 1:9.00003 41.1523 370.37 0.8 0.469 Synergic effect 1:8.99998 123.457 123.457 0.59 0.62 Synergic effect 1:1     370.37 123.457 0.566 0.767 Moderate 1:0.33333 synergic effect 1111.11 123.457 0.606 0.781 Moderate 1:0.11111 synergic effect

TABLE 17 <Antitumor agent: cisplatin, Cancer type: small cell lung cancer, Cell line: NCI-H69> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 1000 625 0.515 0.787 Moderate synergic effect 1:0.63 1000 5000 0.798 0.791 Moderate synergic effect 1:5   1000 10000 0.868 0.847 Moderate synergic effect 1:10  2000 625 0.717 0.582 Synergic effect 1:0.31 2000 1250 0.694 0.783 Moderate synergic effect 1:0.63 2000 2500 0.785 0.679 Synergic effect 1:1.25 2000 5000 0.847 0.681 Synergic effect 1:2.5  2000 10000 0.891 0.763 Moderate synergic effect 1:5  

TABLE 18 <Antitumor agent: cisplatin, Cancer type: non- small cell lung cancer, Cell line: A549> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 22.8624 0.337 0.149 Strong 1:1.66667 synergic effect 13.7174 68.5871 0.321 0.193 Strong 1:5.00001 synergic effect 13.7174 50000 0.752 0.465 Synergic effect   1:3645.00561 41.1523 22.8624 0.302 0.519 Synergic effect 1:0.55556 41.1523 68.5871 0.324 0.484 Synergic effect 1:1.66667 41.1523 50000 0.705 0.837 Moderate   1:1214.99892 synergic effect 123.457 22.8624 0.507 0.516 Synergic effect 1:0.18519 123.457 68.5871 0.5 0.54 Synergic effect 1:0.55555 123.457 50000 0.763 0.517 Synergic effect  1:404.99931 370.37 22.8624 0.797 0.293 Strong 1:0.06173 synergic effect 370.37 68.5871 0.763 0.375 Synergic effect 1:0.18519 370.37 1851.85 0.666 0.722 Moderate 1:5     synergic effect 370.37 16666.7 0.751 0.558 Synergic effect  1:45.00014

TABLE 19 <Antitumor agent: cisplatin, Cancer type: epidermal cancer, Cell line: KB> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 250 313 0.743 0.816 Moderate 1:1.25 synergic effect 250 625 0.871 0.758 Moderate 1:2.5  synergic effect 500 156 0.887 0.608 Synergic effect 1:0.31 500 313 0.932 0.546 Synergic effect 1:0.63 500 625 0.953 0.568 Synergic effect 1:1.25

TABLE 20 <Antitumor agent: cytarabine, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 41.1523 0.357 0.412 Synergic effect 1:3.00001 13.7174 123.457 0.574 0.346 Synergic effect 1:9.00003 13.7174 370.37 0.722 0.408 Synergic effect  1:27.00001 41.1523 41.1523 0.369 0.447 Synergic effect 1:1     41.1523 123.457 0.565 0.393 Synergic effect 1:3     41.1523 370.37 0.695 0.506 Synergic effect 1:8.99998 123.457 41.1523 0.409 0.518 Synergic effect 1:0.33333 123.457 123.457 0.533 0.566 Synergic effect 1:1     123.457 370.37 0.755 0.373 Synergic effect 1:2.99999 370.37 1.52416 0.393 0.774 Moderate 1:0.00412 synergic effect 370.37 13.7174 0.418 0.778 Moderate 1:0.03704 synergic effect 370.37 41.1523 0.65 0.347 Synergic effect 1:0.11111 370.37 123.457 0.78 0.234 Strong 1:0.33333 synergic effect 1111.11 1.52416 0.725 0.592 Synergic effect 1:0.00137 1111.11 4.57247 0.739 0.555 Synergic effect 1:0.00412 1111.11 13.7174 0.698 0.687 Synergic effect 1:0.01235 1111.11 41.1523 0.77 0.5 Synergic effect 1:0.03704

TABLE 21 <Antitumor agent: cytarabine, Cancer type: epidermal cancer, Cell line: A431> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 370.37 0.557 0.831 Moderate  1:27.00001 synergic effect 13.7174 1111.11 0.769 0.55 Synergic effect  1:81.00004 41.1523 370.37 0.56 0.82 Moderate 1:8.99998 synergic effect 41.1523 1111.11 0.769 0.552 Synergic  1:26.99995 effect 123.457 1111.11 0.74 0.712 Moderate 1:8.99998 synergic effect 370.37 370.37 0.594 0.706 Moderate 1:1     synergic effect 1111.11 41.1523 0.325 0.696 Synergic effect 1:0.03704 3333.33 1.52416 0.552 0.512 Synergic effect 1:0.00046 3333.33 4.57247 0.527 0.55 Synergic effect 1:0.00137 3333.33 13.7174 0.596 0.483 Synergic effect 1:0.00412 3333.33 41.1523 0.672 0.425 Synergic effect 1:0.01235 3333.33 123.457 0.688 0.481 Synergic effect 1:0.03704 3333.33 370.37 0.711 0.636 Synergic effect 1:0.11111

TABLE 22 <Antitumor agent: dasatinib, Cancer type: acute myelocytic leukemia, Cell line: Kasumi-1> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 13.7174 0.527 0.265 Strong 1:1     synergic effect 13.7174 41.1523 0.628 0.195 Strong 1:3.00001 synergic effect 13.7174 123.457 0.666 0.298 Strong 1:9.00003 synergic effect 13.7174 370.37 0.668 0.793 Moderate  1:27.00001 synergic effect 41.1523 13.7174 0.534 0.385 Synergic effect 1:0.33333 41.1523 41.1523 0.602 0.368 Synergic effect 1:1     41.1523 123.457 0.648 0.462 Synergic effect 1:3     123.457 13.7174 0.556 0.701 Moderate 1:0.11111 synergic effect 123.457 41.1523 0.683 0.383 Synergic effect 1:0.33333 123.457 123.457 0.65 0.699 Synergic effect 1:1     123.457 370.37 0.711 0.665 Synergic effect 1:2.99999 370.37 41.1523 0.779 0.57 Synergic effect 1:0.11111 370.37 123.457 0.794 0.536 Synergic effect 1:0.33333 370.37 370.37 0.8 0.566 Synergic effect 1:1    

TABLE 23 <Antitumor agent: doxorubicin, Cancer type: small cell lung cancer, Cell line: SBC-1> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 500.0 62.5 0.789 0.542 Synergic effect 1:0.13 500.0 125.0 0.886 0.509 Synergic effect 1:0.25 1000.0 15.6 0.647 0.584 Synergic effect 1:0.02 1000.0 31.3 0.826 0.300 Synergic effect 1:0.03 1000.0 62.5 0.906 0.244 Strong 1:0.06 synergic effect 1000.0 125.0 0.927 0.339 Synergic effect 1:0.13 2000.0 7.8 0.710 0.592 Synergic effect  1:0.0039 2000.0 15.6 0.770 0.474 Synergic effect 1:0.01 2000.0 31.3 0.826 0.412 Synergic effect 1:0.02 2000.0 62.5 0.866 0.437 Synergic effect 1:0.03 2000.0 125.0 0.913 0.449 Synergic effect 1:0.06

TABLE 24 <Antitumor agent: doxorubicin, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 41.1523 0.389 0.356 Synergic effect 1:3.00001 13.7174 123.457 0.581 0.502 Synergic effect 1:9.00003 13.7174 370.37 0.763 0.69 Synergic effect  1:27.00001 41.1523 41.1523 0.433 0.348 Synergic effect 1:1     41.1523 123.457 0.525 0.65 Synergic effect 1:3     123.457 41.1523 0.408 0.534 Synergic effect 1:0.33333 123.457 123.457 0.537 0.719 Moderate 1:1     synergic effect 370.37 13.7174 0.451 0.674 Synergic effect 1:0.03704 370.37 41.1523 0.605 0.493 Synergic effect 1:0.11111 370.37 123.457 0.618 0.753 Moderate 1:0.33333 synergic effect 1111.11 1.52416 0.737 0.618 Synergic effect 1:0.00137 1111.11 4.57247 0.706 0.713 Moderate 1:0.00412 synergic effect 1111.11 13.7174 0.712 0.717 Moderate 1:0.01235 synergic effect 1111.11 41.1523 0.705 0.804 Moderate 1:0.03704 synergic effect

TABLE 25 <Antitumor agent: docetaxel, Cancer type: stomach cancer, Cell line: NCI-N87> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 100 4 0.568 0.807 Moderate 1:0.04 synergic effect 100 8 0.707 0.716 Moderate 1:0.08 synergic effect 200 4 0.731 0.697 Synergic effect 1:0.02 200 8 0.792 0.683 Synergic effect 1:0.04 200 16 0.848 0.709 Moderate 1:0.08 synergic effect 400 4 0.812 0.845 Moderate 1:0.01 synergic effect 400 8 0.85 0.792 Moderate 1:0.02 synergic effect 400 16 0.879 0.816 Moderate 1:0.04 synergic effect

TABLE 26 <Antitumor agent: docetaxel, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 0.457247 0.345 0.761 Moderate 1:0.03333 synergic effect 13.7174 1.37174 0.691 0.21 Strong 1:0.1   synergic effect 13.7174 4.11523 0.791 0.257 Strong 1:0.3   synergic effect 41.1523 1.37174 0.71 0.206 Strong 1:0.03333 synergic effect 41.1523 4.11523 0.789 0.279 Strong 1:0.1   synergic effect 123.457 1.37174 0.651 0.407 Synergic effect 1:0.01111 370.37 1.37174 0.758 0.374 Synergic effect 1:0.0037  1111.11 0.152416 0.787 0.679 Synergic effect 1:0.00014

TABLE 27 <Antitumor agent: docetaxel, Cancer type: non-small cell lung cancer, Cell line: NCI-H226> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 500 1.25 0.640 0.265 Strong  1:0.0025 synergic effect 500 2.50 0.723 0.195 Strong 1:0.01 synergic effect 500 5.00 0.803 0.135 Strong 1:0.01 synergic effect 500 10.00 0.852 0.110 Strong 1:0.02 synergic effect 500 20.00 0.855 0.157 Strong 1:0.04 synergic effect 1000 1.25 0.538 0.771 Moderate  1:0.0013 synergic effect 2000 1.25 0.673 0.710 Moderate   1:0.00063 synergic effect

TABLE 28 <Antitumor agent: docetaxel, Cancer type: epidermal cancer, Cell line: A431> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 0.457247 0.281 0.681 Synergic effect 1:0.03333 13.7174 1.37174 0.618 0.129 Strong 1:0.1   synergic effect 13.7174 4.11523 0.766 0.097 Extremely strong 1:0.3   synergic effect 41.1523 0.457247 0.281 0.705 Moderate 1:0.01111 synergic effect 41.1523 1.37174 0.645 0.108 Strong 1:0.03333 synergic effect 41.1523 4.11523 0.751 0.116 Strong 1:0.1   synergic effect 123.457 1.37174 0.604 0.167 Strong 1:0.01111 synergic effect 123.457 4.11523 0.724 0.162 Strong 1:0.03333 synergic effect 370.37 1.37174 0.435 0.693 Synergic effect 1:0.0037  370.37 4.11523 0.589 0.56 Synergic effect 1:0.01111 3333.33 0.152416 0.653 0.562 Synergic effect 1:0.00005 3333.33 0.457247 0.663 0.555 Synergic effect 1:0.00014 3333.33 1.37174 0.672 0.584 Synergic effect 1:0.00041 3333.33 4.11523 0.709 0.59 Synergic effect 1:0.00123

TABLE 29 <Antitumor agent: paclitaxel, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 4.11523 0.651 0.313 Synergic effect 1:0.3   41.1523 4.11523 0.625 0.38 Synergic effect 1:0.1   123.457 4.11523 0.615 0.454 Synergic effect 1:0.03333 370.37 4.11523 0.598 0.667 Synergic effect 1:0.01111 1111.11 0.152416 0.601 0.777 Moderate 1:0.00014 synergic effect 1111.11 1.37174 0.637 0.778 Moderate 1:0.00123 synergic effect 1111.11 4.11523 0.79 0.469 Synergic effect 1:0.0037 

TABLE 30 <Antitumor agent: paclitaxel, Cancer type: non-small cell lung cancer, Cell line: NCI-H2170> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 100 2.00 0.574 0.669 Synergic effect 1:0.02 100 4.00 0.746 0.528 Synergic effect 1:0.04 100 8.00 0.821 0.579 Synergic effect 1:0.08 200 2.00 0.753 0.576 Synergic effect 1:0.01 200 4.00 0.832 0.507 Synergic effect 1:0.02 200 8.00 0.891 0.475 Synergic effect 1:0.04 400 2.00 0.871 0.590 Synergic effect 1:0.01 400 4.00 0.892 0.577 Synergic effect 1:0.01 400 8.00 0.912 0.593 Synergic effect 1:0.02

TABLE 31 <Antitumor agent: paclitaxel, Cancer type: epidermal cancer, Cell line: A431> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 4.11523 0.675 0.281 Strong 1:0.3 synergic effect 41.1523 4.11523 0.643 0.357 Synergic effect 1:0.1 41.1523 12.3457 0.777 0.367 Synergic effect 1:0.3 123.457 4.11523 0.636 0.386 Synergic effect   1:0.03333 123.457 12.3457 0.8 0.3 Synergic effect 1:0.1 370.37 4.11523 0.553 0.714 Moderate   1:0.01111 synergic effect 370.37 12.3457 0.766 0.432 Synergic effect   1:0.03333

TABLE 32 <Antitumor agent: vemurafenib, Cancer type: malignant melanoma, Cell line: A375> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 123.457 0.367 0.651 Synergic effect 1:9.00003 13.7174 370.37 0.494 0.768 Moderate  1:27.00001 synergic effect 41.1523 123.457 0.343 0.84 Moderate 1:3     synergic effect 41.1523 370.37 0.492 0.811 Moderate 1:8.99998 synergic effect

TABLE 33 <Antitumor agent: pemetrexed, Cancer type: large intestine cancer, Cell line: HCT-116a> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 123.457 0.215 0.386 Synergic effect 1:9.00003 13.7174 370.37 0.436 0.238 Strong  1:27.00001 synergic effect 13.7174 1111.11 0.534 0.379 Synergic effect  1:81.00004 13.7174 3333.33 0.623 0.643 Synergic effect  1:243.00013 41.1523 370.37 0.388 0.358 Synergic effect 1:8.99998 41.1523 1111.11 0.526 0.424 Synergic effect  1:26.99995 41.1523 3333.33 0.621 0.672 Synergic effect  1:80.99985 123.457 1111.11 0.484 0.633 Synergic effect 1:8.99998 370.37 1.52416 0.337 0.662 Synergic effect 1:0.00412 370.37 4.57247 0.387 0.565 Synergic effect 1:0.01235 370.37 13.7174 0.278 0.835 Moderate 1:0.03704 synergic effect 370.37 41.1523 0.33 0.724 Moderate 1:0.11111 synergic effect 370.37 123.457 0.324 0.84 Moderate 1:0.33333 synergic effect 370.37 370.37 0.499 0.55 Synergic effect 1:1     1111.11 1.52416 0.726 0.578 Synergic effect 1:0.00137 1111.11 4.57247 0.714 0.605 Synergic effect 1:0.00412 1111.11 13.7174 0.729 0.573 Synergic effect 1:0.01235 1111.11 41.1523 0.745 0.541 Synergic effect 1:0.03704 1111.11 123.457 0.75 0.537 Synergic effect 1:0.11111 1111.11 370.37 0.764 0.524 Synergic effect 1:0.33333 1111.11 1111.11 0.721 0.697 Synergic effect 1:1     1111.11 3333.33 0.749 0.79 Moderate 1:3     synergic effect

TABLE 34 <Antitumor agent: pemetrexed, Cancer type: epidermal cancer, Cell line: A431> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 123.457 0.554 0.273 Strong 1:9.00003 synergic effect 13.7174 370.37 0.638 0.38 Synergic effect  1:27.00001 13.7174 1111.11 0.697 0.636 Synergic effect  1:81.00004 41.1523 123.457 0.509 0.409 Synergic effect 1:3     41.1523 370.37 0.617 0.466 Synergic effect 1:8.99998 3333.33 1.52416 0.536 0.551 Synergic effect 1:0.00046 3333.33 4.57247 0.554 0.537 Synergic effect 1:0.00137 3333.33 13.7174 0.54 0.576 Synergic effect 1:0.00412 3333.33 41.1523 0.534 0.657 Synergic effect 1:0.01235 3333.33 123.457 0.565 0.761 Moderate 1:0.03704 synergic effect 3333.33 370.37 0.656 0.744 Moderate 1:0.11111 synergic effect

TABLE 35 <Antitumor agent: bortezomib, Cancer type: multiple myeloma, Cell line: RPMI-8226> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 400 0.5 0.4 0.832 Moderate 1:0.00125 synergic effect 800 0.5 0.75 0.662 Synergic effect 1:0.00063 800 0.8 0.75 0.721 Moderate 1:0.001  synergic effect 800 1 0.77 0.719 Moderate 1:0.00125 synergic effect

TABLE 36 <Antitumor agent: mitomycin C, Cancer type: large intestine cancer, Cell line: HCT-116> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 500.0 12.5 0.879 0.757 Moderate 1:0.025 synergic effect

TABLE 37 <Antitumor agent: lapatinib, Cancer type: stomach cancer, Cell line: NCI-N87> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 250 3.90625 0.728 0.658 Synergic effect 1:0.016 250 7.8125 0.746 0.692 Synergic effect 1:0.031 250 15.625 0.784 0.707 Moderate 1:0.063 synergic effect 250 31.25 0.810 0.818 Moderate 1:0.125 synergic effect

TABLE 38 <Antitumor agent: lapatinib, Cancer type: breast cancer, Cell line: UACC-893> Antitumor Con- Compound agent comitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 1000 62.5 0.590 0.511 Synergic effect 1:0.06 1000 125 0.643 0.362 Synergic effect 1:0.13 1000 250 0.629 0.613 Synergic effect 1:0.25 1000 500 0.715 0.494 Synergic effect 1:0.5  1000 1000 0.726 0.848 Moderate 1:1   synergic effect 2000 62.5 0.665 0.344 Synergic effect 1:0.03 2000 125 0.710 0.246 Strong 1:0.06 synergic effect 2000 250 0.737 0.269 Strong 1:0.13 synergic effect 2000 500 0.749 0.403 Synergic effect 1:0.25 2000 1000 0.761 0.661 Synergic effect 1:0.5  4000 62.5 0.708 0.333 Synergic effect 1:0.02 4000 125 0.709 0.384 Synergic effect 1:0.03 4000 250 0.712 0.480 Synergic effect 1:0.06 4000 500 0.746 0.488 Synergic effect 1:0.13 4000 1000 0.783 0.576 Synergic effect 1:0.25 8000 62.5 0.702 0.666 Synergic effect 1:0.01 8000 125 0.722 0.542 Synergic effect 1:0.02 8000 250 0.726 0.611 Synergic effect 1:0.03 8000 500 0.754 0.575 Synergic effect 1:0.06 8000 1000 0.775 0.711 Moderate 1:0.13 synergic effect

TABLE 39 <Antitumor agent: lenalidomide, Cancer type: multiple myeloma, Cell line: MM.1S> Antitumor Compound agent Concomitant 1 (nM) (nM) Fa CI CI_COMMENT ratio 13.7174 15.2416 0.227 0.657 Synergic effect 1:1.11111 13.7174 45.7247 0.323 0.551 Synergic effect 1:3.33334 13.7174 137.174 0.493 0.284 Strong 1:10    synergic effect 13.7174 411.523 0.618 0.225 Strong  1:30.00007 synergic effect 13.7174 1234.57 0.735 0.168 Strong  1:90.00029 synergic effect 13.7174 3703.7 0.765 0.293 Strong  1:270.00015 synergic effect 13.7174 11111.1 0.776 0.693 Synergic effect  1:810.00044 41.1523 15.2416 0.244 0.806 Moderate 1:0.37037 synergic effect 41.1523 45.7247 0.376 0.523 Synergic effect 1:1.11111 41.1523 137.174 0.536 0.329 Synergic effect 1:3.33333 41.1523 411.523 0.652 0.263 Strong 1:10    synergic effect 41.1523 1234.57 0.756 0.206 Strong  1:30.00002 synergic effect 41.1523 3703.7 0.777 0.317 Synergic effect  1:89.99983 123.457 137.174 0.552 0.67 Synergic effect 1:1.11111 123.457 411.523 0.693 0.463 Synergic effect 1:3.33333 123.457 1234.57 0.788 0.352 Synergic effect 1:10   

Incidentally, gemcitabine exhibited the same synergic effect as in NCI-H522 even in other non-small cell lung cancers (NCI-H441, NCI-H520). Cisplatin exhibited the same synergic effect as in A549 even in other non-small cell lung cancers (NCI-H2170, NCI-H226, NCI-H441, NCI-H520, NCI-H522, PC-14). Doxorubicin exhibited the same synergic effect as in SBC-1 even in other small cell lung cancers (NCI-N417). Docetaxel exhibited the same synergic effect as in NCI-H226 even in other non-small cell lung cancers (NCI-H2170). Paclitaxel exhibited the same synergic effect as in NCI-H2170 even in other non-small cell lung cancers (HCC827, NCI-H1975). Lapatinib exhibited the same synergic effect as in UACC-893 even in other breast cancers (BT-474, JIMT-1, MDA-MB-361, MDA-MB-453, SK-BR-3, UACC-812).

As described above, it was clearly found that the azabicyclo compound of the invention or a salt thereof exhibited a strong synergic effect with extremely various ranges of antitumor agents having different action mechanisms. 

The invention claimed is:
 1. A method for potentiating an antitumor effect of an antitumor agent, comprising: administering to a patient 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof and the antitumor agent selected from the group consisting of docetaxel, paclitaxel, cisplatin, amrubicin, crizotinib, 5-fluorouracil (5-FU), 5-(4-bromo-2-chlorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamic acid 2-hydroxyethyl ester (ZD6244), 7-ethyl-10-hydroxycamptothecin (SN-38), imatinib, etoposide, erlotinib, oxaliplatin, gefitinib, gemcitabine, cytarabine, dasatinib, doxorubicin, vemurafenib, pemetrexed, bortezomib, mytomycin C, lapatinib, and lenalidomide, wherein a molar ratio of the 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof to the antitumor agent is from 1:0.00014 to
 3645. 2. The method of claim 1, wherein the antitumor agent is at least one selected from the group consisting of amrubicin, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cytarabine, pemetrexed, paclitaxel, docetaxel, etoposide, lenalidomide, imatinib, gefitinib, dasatinib, erlotinib, lapatinib, and crizotinib.
 3. The method of claim 1, wherein the patient has at least one tumor selected from the group consisting of head and neck cancer, esophageal cancer, stomach cancer, duodenal cancer, liver cancer, gallbladder/bile duct cancer, pancreatic cancer, small intestinal cancer, colorectal cancer, colon cancer, rectal cancer, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine corpus cancer, kidney cancer, bladder cancer, prostate cancer, malignant melanoma, epidermal cancer, multiple myeloma, acute myelocytic leukemia, and large intestine cancer.
 4. The method of claim 1, wherein the antitumor agent and the 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof are administered to the patient simultaneously or separately.
 5. The method of claim 1, wherein the salt of 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide is at least one selected from the group consisting of an acid addition salt of an inorganic acid, an acid additional salt of an organic acid, a salt of an inorganic base, a salt of an organic base, a salt of a basic amino acid, and an ammonium salt.
 6. The method of claim 1, wherein the antitumor agent is at least one of docetaxel and paclitaxel.
 7. The method of claim 1, wherein the antitumor agent is at least one of docetaxel and paclitaxel, and a molar ratio of the 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof to the antitumor agent is from 1:0.00014 to 0.3.
 8. The method of claim 1, wherein the antitumor agent is administered to the patient prior to administering the 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[34-b]pyridin-1-yl}benzamide or a salt thereof to the patient.
 9. The method of claim 1, wherein the patient has at least one tumor, and the antitumor agent is effective for treating the tumor.
 10. The method of claim 1, wherein the patient has at least one tumor selected from the group consisting of head and neck cancer, digestive organ cancer, lung cancer, breast cancer, ovarian cancer, uterus cancer, kidney cancer, bladder cancer, prostate cancer, skin cancer, and blood cancer.
 11. The method of claim 1, wherein the patient has at least one tumor selected from the group consisting of lung cancer, stomach cancer, epidermal cancer, malignant melanoma, acute myelocytic leukemia, large intestine cancer, gallbladder cancer, multiple myeloma, and breast cancer. 